Topical drug delivery strategies for enhancing drug effectiveness by skin barriers, drug delivery systems and individualized dosing

Topical drug delivery is widely used in various diseases because of the advantages of not passing through the gastrointestinal tract, avoiding gastrointestinal irritation and hepatic first-pass effect, and reaching the lesion directly to reduce unnecessary adverse reactions. The skin helps the organism to defend itself against a huge majority of external aggressions and is one of the most important lines of defense of the body. However, the skin’s strong barrier ability is also a huge obstacle to the effectiveness of topical medications. Allowing the bioactive, composition in a drug to pass through the stratum corneum barrier as needed to reach the target site is the most essential need for the bioactive, composition to exert its therapeutic effect. The state of the skin barrier, the choice of delivery system for the bioactive, composition, and individualized disease detection and dosing planning influence the effectiveness of topical medications. Nowadays, enhancing transdermal absorption of topically applied drugs is the hottest research area. However, enhancing transdermal absorption of drugs is not the first choice to improve the effectiveness of all drugs. Excessive transdermal absorption enhances topical drug accumulation at non-target sites and the occurrence of adverse reactions. This paper introduces topical drug delivery strategies to improve drug effectiveness from three perspectives: skin barrier, drug delivery system and individualized drug delivery, describes the current status and shortcomings of topical drug research, and provides new directions and ideas for topical drug research.

1 Introduction

Topical drugs have a long history. Thousands of years ago, ointments and salves made from animal, mineral, or plant extracts were commonly used in Egyptians, Chinese and Babylonians to cure a wide range of ailments (Lima et al., 2021; Metwaly et al., 2021; Roberts et al., 2021). Before 2000 BC, emplastra appeared in China, which maybe the original transdermal patch (Pastore et al., 2015). Many topical drugs are so effective that they are now widely used in many countries, and are also the source of discovery of some very effective monomers. However, there are some topical drugs that seem somewhat incomprehensible nowadays. For example, Kahun gynecological papyrus records that a substance (possibly crocodile excrement) is treated with honey or kefir and injected into the vagina for contraception (Metwaly et al., 2021). During the period of using natural drugs to treat diseases, external medication is one of the most important means of treating diseases. Surviving frescoes and books attest to this (Pastore et al., 2015; Chen, 2016; Zheng and Zheng, 2017). In terms of enhancing the effectiveness of topical drugs, many attempts have been made and many useful results have been achieved. Ancient Egyptians added essential oils to perfumes or ointments to increase the transdermal absorption efficiency of the active ingredients (Elshafie and Camale, 2017); Chinese used wine to soak their medicines to realize the enrichment of the active ingredients and to increase the transdermal absorption efficiency of the active ingredients (Zhu, 2007); and Chinese also heated up topical medicines added with iron sand to be used after application, which is a kind of topical drug formulation design to enhance the therapeutic efficacy of the medicines by heating (Zhu, 2007). In 1860, German chemist Niemann extracted an alkaloid from coca leaves and named it as cocaine. This is the first small molecule topical drug that is generally recognized. In 1884, cocaine was first officially used as a local anesthetic in clinical practice (Grzybowski, 2008). Since then, small molecule drugs have become the overlord of topical drugs to replace natural medicines (Figure 1).

FIGURE 1

FIGURE 1. Development process of traditional topical drugs. The development process is divided into four aspects: topical medicine has a long history, topical drugs play an important role, the ancients can improve the efficacy of topical drugs, and topical drugs have begun a new era.

With the continuous development of science and technology and people’s deepening of disease understanding, peptides, proteins, nucleic acids, cells and bacteria are gradually used as drugs. The ultimate goal of all topical medication is to reach the target site in vivo with enough dose without side effects. According to the different target sites, topical medication can be divided into four types: 1) Drugs that do not want to be absorbed (e.g., sunscreen, heavy metals); 2) Drugs that reach the skin tissue and do not want to spread (e.g., drugs for the treatment of skin diseases); 3) Drugs that reach deeper tissues (e.g., anesthetics, drugs for treating muscle or joint diseases); 4) Drugs that cross the skin into blood vessels and are transported to other tissues or organs (e.g., insulin). In this paper, diseases are divided into three categories according to different target sites of disease (Table 1).

TABLE 1

TABLE 1. Classification of diseases at different target sites for topical drugs.

2 Properties and functions of four different skin barriers

Recently, our view of the skin has evolved from a mere physical barrier to an organic organ made up of microbial, chemical, physical and immune barriers (Eyerich et al., 2018). Microbial, physical, chemical and immune barriers work synergistically together to maintain homeostasis in the body (Figure 2).

FIGURE 2

FIGURE 2. The balance of the four skin barriers is the key to healthy skin. The four skin barriers are closely related and do not exist in isolation. Abnormalities in the microbiological and physical barriers are often the beginning of disease, and their abnormalities cause changes in the immune and chemical barriers. Only when all four barriers are restored to balance will the skin return to normal.

The microbial barrier consists of bacteria, archaea, fungi and viruses which inhabit the surface of the skin and mucous membranes. The microbial barrier can maintain and enhance the skin barrier function through a variety of mechanisms such as competing for nutrients, secreting metabolites, and interfering with the quorum sensing system, inhibiting conditional pathogenic bacterial infection (Uberoi et al., 2021), regulating immunity (Dhariwala and Scharschmidt, 2021), and promoting cell and tissue regeneration (Wang et al., 2023). For example, Staphylococcus epidermidis can affect immune cells in a number of ways thereby promoting neonatal skin barrier development (Severn and Horswill, 2023), enhancing innate immunity and inhibiting invasion by pathogenic bacteria (Gallo, 2015). Balancing the microbial barrier is key to maintaining healthy skin. Not only can increased abundance of pathogenic bacteria cause or exacerbate disease, but also can non-pathogenic bacteria (Severn and Horswill, 2023). And pathogenic bacteria are not entirely harmful. Under homeostatic conditions, the immune response induced by Staphylococcus aureus colonization of skin tissue can promote the growth of damaged nerve axons and local nerve regeneration (Enamorado et al., 2023).

The physical barrier is made up of the cells that make up the structure of the skin and is divided into epidermis, dermis and subcutaneous tissue. They balance body temperature and moisture, protect the body from ultraviolet exposure, transmit sensations and maintain good health (Eyerich et al., 2018). The stratum corneum is the outermost layer of the epidermis, with a thickness of about 10–20 μm, high density, low water content, low surface area of solute transport, and inactive metabolism, which is figuratively likened to a “brick wall structure” (Yang et al., 2017). The epidermis is mainly composed of keratinocytes with different degrees of differentiation. The keratinocytes move upwards from the basal layer, the degree of differentiation increases, the cells continue to age until they die, and the dead cells eventually accumulate in the outermost layer to form the stratum corneum (Peskoller et al., 2022). The dermis is located below the epidermis, and the basal layer is connected to the dermis layer by means of a basement membrane, which is mainly composed of fibroblasts and plays a supporting role in the epidermis (Ogawa, 2017). Cushioning the epidermis and dermis are layers of subcutaneous tissue and fat that protect the body from damage, provide flexibility and strength, act as a barrier to infection, and act as heat insulation and shock absorption (Singh and Singh, 1993). There are also skin appendages such as hair follicles, sebaceous glands, sweat glands, and nails on the surface of the skin, many of which are directly connected to the dermis and are an important way for drugs, especially macromolecular drugs, to enter the blood. Hair follicles are highly conserved sensory organs that are important reservoirs of keratinocytes and melanocytes in the skin, and hair follicles are also implicated in immune response to pathogens, thermoregulation, sebum production, angiogenesis, neurogenesis and wound healing (Ji et al., 2021). Sebaceous gland is a component of the sebaceous gland unit of the hair follicle, which secretes sebum, and its state is related to hair follicle morphogenesis (Zouboulis et al., 2022). The human body has about 20,000 to 40,000 sweat glands, which are divided into apocrine sweat glands and eccrine sweat glands according to anatomical structure and location (Sato et al., 1989). The end of the exocrine sweat duct is on the surface of the skin, and the end of the apocrine sweat duct is in the hair follicle.

The chemical barrier consists of metabolites from skin cells and microorganisms, and the chemical composition of the barrier varies from site to site, but they all play an important role in maintaining the balance of the skin barrier. The epidermis contains ceramides, free fatty acids, cholesterol, cholesterol sulphates, cholesterol esters and other lipids that are important for maintaining the barrier function of the skin (Starr et al., 2022). The research shows that the skin barrier function is significantly reduced after stratum corneum lipid extraction (Sweeney and Downing, 1970). The main components in sebum are mainly composed of glycerol ester, free fatty acid, cholesterol, Cholesteryl ester, wax ester and marlene. They are skin lubricants and stratum corneum plasticizing lipids, which can maintain the acidic condition of the outer surface of the skin and enhance the skin barrier function, and also play a central role in the composition and functional regulation of the skin microbiome (Qiu et al., 2022; Yin et al., 2023). Dysregulation of sebum secretion is an crucial cause or exacerbation of inflammatory skin disease (Shi et al., 2015). Amino acids, sodium pyrrolidone carboxylate, lactate, urea and other composition with moisturizing functions produced by the disintegration of keratinocytes are called natural moisturizing factors. Natural moisturizing factors are mainly distributed in the stratum corneum, which can regulate the hydration function of keratinocytes, maintain normal skin permeability, and reduce percutaneous water loss of the skin (Mojumdar et al., 2017). The metabolites of microorganisms mainly play a regulatory role. For example, sphingomyelinase can increase ceramide content in the stratum corneum, reduce skin dehydration, and enhance skin barrier integrity (Zheng et al., 2022). Short-chain fatty acids can regulate inflammation and promote wound healing (Stacy and Belkaid, 2019). Sweat glands producing hypotonic solutions can regulation and skin hydration (Roberts et al., 2021). These hypotonic solutions, together with other substances on the surface of the skin, constitute hundreds of components of sweat, and these components can reflect the state of the body (Yang et al., 2023). There is growing evidence that sweat can become a new type of substance to be tested, which can be used to detect diseases or special conditions such as alcohol or drug use.

The immune barrier is an inflammation immune regulatory system composed of various immune cells and inflammatory molecules in the skin. Under normal circumstances, only a small percentage of immune cells reside between the skin tissues. These immune cells residing among skin tissues can respond immediately when the skin is attacked by external forces, such as Langerhans cell and memory cells, which maintain skin stability by secreting antibodies, splitting cells, phagocytosis of pathogens and other means (Kabashima et al., 2019). Microorganisms are an important source for the immune barrier to respond appropriately to stimuli. The moist is an excellent place for microorganisms to communicate with the immune system (Chen et al., 2018). The skin is composed of microorganisms, cells, and the chemicals they secrete. It is an organic whole, and changes in every link can cause skin diseases. The cross-era development of biotechnology has focused research on the single-cell level, and breakthroughs in the analysis of very small samples of nucleic acids, proteins, small molecule compounds and other components have allowed us to deepen our understanding of the occurrence and development of diseases. Cell activity in disease states is summarized here, as detailed in Table 2. Understanding the dynamic changes of different cells in the occurrence and development of diseases is conducive to patients to choose more suitable drugs in different disease states, and improve effectiveness, increase the cure rate of patients, and reduce the pain of patients by actively avoiding drugs with poor effects, or through some measures to improve the efficiency of drugs reaching the target site.

TABLE 2

TABLE 2. The role of different cells in skin diseases.

3 Drug delivery systems and factors affecting transdermal drug absorption

Drug delivery system refers to a technological system that comprehensively regulates the distribution of drugs in an organism in terms of space, time and dose (Baryakova et al., 2023). Ideally, the drug delivery system should allow accumulation of the bioactive composition in the target site at the appropriate dose without overpenetration resulting in the drug reaching the circulation at a toxic dose or accumulating in tissues at non-target sites causing adverse effects (Peralta et al., 2018). Physicochemical properties of drug bioactive composition, excipients and additives, such as molecular weight, partition coefficient, polarity, surface charge and degree of hydrogen bonding, affect the absorption efficiency of drug bioactive composition (Mohammed et al., 2022). Selection of appropriate dosage forms, carriers, additives, and some smart response elements can improve the problems of poor stability, low solubility, and inability to accumulate at the target site of the drug bioactive composition (Figure 3). Garg et al. have given a very detailed account of the commonly used topical dosage forms and additives in their article. So this paper do not cover these two aspects (Garg et al., 2015).

FIGURE 3

FIGURE 3. Drug carriers and drug stimulus response elements. (A) is the 12 drug carriers described in the text, which are cell-penetrating peptides, hydrogels, microsponges, polymer films, ionic liquids, deep eutectic solvents, liquid crystals, metal-organic frameworks, bacteria and bacterial derivatives, cells and cell derivatives, silicon dioxide, and calcium carbonate. (B) is the stimulus response element for five drugs described in the text, namely, ligand-mediated targeting of drug-smart response elements, pH-responsive smart response element, redox-responsive smart response element, enzyme-responsive smart response element, and magnetically-responsive drug smart response element.

3.1 Drug carriers

When the bioactive composition of a drug is poorly stabilized, low solubility, dose-limiting side effects, a narrow therapeutic window or short half-life that makes it difficult to maintain the proper concentration of the drug over a period of time, the choice of the right drug delivery system is an important way to address these issues. Ramanunny et al. described 16 drug delivery systems (Ramanunny et al., 2021). This paper builds on them with a further account of 16 drug carriers (Table 3).

TABLE 3

TABLE 3. Advantages, disadvantages and applications of drug carriers.

3.1.1 Cell-penetrating peptides

Cell-penetrating peptides, also known as protein translocation structural domains, membrane translocation sequences, or trojan peptides, are small molecules of 6–30 amino acid residues that are able to penetrate biological barriers and cell membranes to enter the cell in a noninvasive manner (Silva et al., 2019). In 1988, Frankel et al. found that the tat protein of human immunodeficiency virus I was taken up into the nucleus by cells grown in tissue cultures (Frankel and Pabo, 1988). Since then, people have begun to take notice of cell-penetrating peptides. Over the course of more than 30 years, the family of cell-penetrating peptides has grown, with more than 100 cell-penetrating peptides described in articles by Milletti alone (Milletti, 2012). Cell-penetrating peptides are classified in a variety of ways. According to their physicochemical properties, cell-penetrating peptides can be simply divided into three categories: cationic, amphipathic and hydrophobic (Raucher and Ryu, 2015). The lack of cell type specificity of cell-penetrating peptides is one of the main reasons preventing their widespread use (Bode Lowik, 2017). The mechanism by which cell-penetrating peptides enter the cell has been the subject of extensive academic interest, but the pathways involved in the process has not been fully elucidated. The mechanisms of cell-penetrating peptide entry into cells identified so far are direct translocation and endocytosis (Guidotti et al., 2017). Cell-penetrating peptide-drug couplers play an important role in the delivery of a wide range of drugs.

3.1.2 Polymer drug delivery systems

Polymers play an important role in drug delivery due to their numerous types, unique three-dimensional structure, high drug loading capacity, and stable physicochemical properties. Polymers have evolved over the past few decades and have appeared in various forms such as hydrogels, polymeric films, and polymeric micelles. Polymers can be categorized into natural and synthetic polymers according to their origin. Natural polymers such as DNA, RNA, and peptides are widely used in bioengineering and drug delivery due to their unique properties (e.g., encodable, biodegradable). With the development of technology, advances in polymer modification techniques and the emergence of 3D printing technology, synthetic polymer carriers are becoming more versatile and powerful.

3.1.2.1 Hydrogels

Hydrogels are highly porous crosslinked three-dimensional hydrophilic polymer networks of drug carriers that can swell by absorbing large amounts of water (Jindal et al., 2022). The presence of hydrophilic groups such as -CONH_2, CONH-, -OH, -COOH, -SO₃H, etc., is the main reason why hydrogels can absorb water and swell. In addition to their shared properties, hydrogels have individualized advantages based on their specific material. For example, chitosan and chitin have antimicrobial properties in their own right. So the antimicrobial capacity of gels based on them is further enhanced (Li et al., 2018). Guanine phosphate can stimulate innate immunity by binding to Toll-like receptor 9, and recognition of DNA hydrogels containing unmethylated cytosine-phosphate-guanine dinucleotides further enhances organismal immunity (Nishikawa et al., 2014). Biomaterials such as DNA and proteins, because of their encodable properties and similarity to the organism’s microenvironment, can cause some programmed changes in the gel, such as the spontaneous formation of artificial protein scaffolds (Sun et al., 2014). In addition, hydrogel materials can be further enhanced by adding functional groups or incorporating some functional materials to further enhance certain properties. Zhou et al. used a biomimetic mineral plastic of calcium carbonate and polyacrylic acid to give the gel optical properties (Zhou et al., 2020). Haraguchi et al. interwoven polymer and clay into a network to create a hydrogel that can repair itself after damage (Haraguchi et al., 2011). The incorporation of high aspect ratio nanoparticles into suitable gel materials can produce shear-thinning hydrogels, and they can protect cells from high shear forces, leading to a wide range of applications in cartilage tissue regeneration and cell delivery for 3D bioprinting (Thakur et al., 2016).

3.1.2.2 Microsponges

Microsponges are a new type of drug delivery vehicle of porous polymer microspheres developed in recent years, usually consisting of crosslinked polymers with adsorbent capacity and containing a very large number of porous microspheres ranging from 5 to 300 μm inside, which can adsorb and encapsulate a large number of bioactive composition (Rahman et al., 2022; Tiwari et al., 2022). The microsponges ensure that the drug is localized on the skin surface and within the epidermis and does not diffuse in large quantities to non-diseased areas, preventing toxic effects caused by excessive accumulation of bioactive composition in the epidermis and dermis (Grabow and Jaeger, 2012). Green et al. used bionic microsponges to generate aggregates of inorganic particles that can provide surfaces and structures for cell attachment, organization and promote matrix synthesis (Green et al., 2020).

3.1.2.3 Polymeric films

Polymer films, which are films made from polymer fibers, have great potential as topical drug carriers. Electrospinning is the fabrication of organized filaments of polymer nanofiber solutions under strong electric field forces, and the resulting fibers have finer diameters (0.1–100 nm) and larger surface areas than those obtained by conventional spinning methods (Bhardwaj and Kundu, 2010). The throughput of nanofibers has become a serious bottleneck limiting their application (Bhardwaj and Kundu, 2010). 3D printing is the latest technology for manufacturing polymeric films. 3D printing is a technology that uses virtual computer-aided design models to create physical objects by depositing successive layers (Economidou et al., 2018). By 3D printing, it is possible to create polymer films with different porosity, mechanical properties and drug loading to meet the needs of topical drug delivery in different situations. The need for materials with low viscosity, droplet size, lack of precision in positioning, high cost and long production time are factors that limit the widespread use of 3D printing technology for polymer films (Riccio et al., 2022).

3.1.3 Ionic liquids

Ionic liquids are a new type of carrier, and everyone does not define it exactly the same way. Lei et al. considered ionic liquids to be compounds composed entirely of ions with melting points below 100°C (Lei et al., 2017). Gomes et al. considered ionic liquids as salts formed from organic cations and organic or inorganic anions (Gomes et al., 2021). Unlike conventional salts, it has unique physical and chemical properties. Although the definitions of ionic liquids are not identical, there is no doubt that ionic liquids are liquid salts at ambient temperature. Based on their chemical structure and properties, ionic liquids can be categorized into three groups: water- and air-sensitive ionic liquids, water- and air-insensitive ionic liquids, and biodegradable ionic liquids (Egorova et al., 2017). There are three applications of ionic liquids in increasing transdermal absorption of drugs: 1) Ionic liquids can be used as skin penetration enhancers for pharmaceutical formulations or in combination with other drug carriers. For example, the combination of ionic liquids and gels to form ionic liquid gels has been shown to be very effective in the treatment of infections and haemostasis (Luo et al., 2022; Gao et al., 2023). The mechanism by which ionic liquids promote transdermal absorption of drugs is not well understood, but may be negatively correlated with ionic interactions (Tanner et al., 2019). 2) The ionic liquid binds to the drug to form a drug-ionic liquid coupling. The essence of this approach is to convert the drug into a liquid salt so that the drug is characterized by the high stability and solubility of a liquid salt. Moshikur et al. combined 12 hydrophilic drugs with oil-soluble ionic liquids, which significantly increased the transdermal absorption of the drugs and significantly increased the elimination half-life and plasma concentration (Md Moshikur et al., 2022). 3) The ionic liquids are constructed by physical or chemical cross-linking to form new drug delivery systems poly-ionic liquids, such as poly-ionic liquid hydrogels.

3.1.4 Deep eutectic solvents

Deep eutectic solvents are novel liquids made by mixing high melting point salts and molecular hydrogen bond donors, which can significantly change the melting point, solubility and biostability of drugs (McDonald et al., 2018). Deep eutectic solvents are usually composed of two or three inexpensive and safe components, which are capable of joining with each other through hydrogen bonding interactions to form low eutectic mixtures, and deep eutectic solvents with a high melting point are also chosen for some thermally unstable drugs to enhance the thermal stability of the drug (Zhang et al., 2012; Kumar and Nanda, 2018). However, how deep eutectic solvents promote transdermal drug absorption has been inconclusive. Boscariol et al. found that choline geranate deep eutectic solvent may have contributed to the penetration of bioactive molecules through the openings by sliding around the fatty compounds that make up the interstitial space between keratinocytes and by creating small transient openings in the cell membrane (Boscariol et al., 2021). However, the resulting small transient openings in the cell membrane did not cause damage to the skin tissue structure. In addition to this deep eutectic solvents can be involved in the stimulation of important components of the response element for precise drug delivery (Shi et al., 2022). Perhaps 1 day we will be able to use deep eutectic solvents to better achieve precise localization and dose control of transdermal drug absorption.

3.1.5 Liquid crystals

Liquid crystals are a state of matter between a solid and a liquid, having both fluidity like a liquid and an orderly arrangement of crystals (Dierking and Al-Zagana, 2017). In 1957, Brown and Shaw described the physical properties of liquid crystals in their book (Mitov, 2017). Liquid crystals can be classified into a number of categories based on the conditions under which the liquid crystal state is maintained. The most commonly used classification of liquid crystals is the division of liquid crystals into thermotropic liquid crystals, which maintain the liquid crystal state within a certain temperature range; and lyotropic liquid crystals, which maintain the liquid crystal phase state under specific concentration conditions. The difficulty in realizing thermotropic liquid crystals at ambient temperature is the reason why almost no thermotropic liquid crystals are used in drug delivery systems. However, it has recently been found that thermotropic liquid crystals can alter the spontaneous water flux at the liquid crystal phase and interface by changing the type and concentration of the added electrolyte, further reorienting the liquid crystals at the aqueous interface and thus releasing the substances stored in the liquid crystals (Ramezani-Dakhel et al., 2017). In this way, thermotropic liquid crystals have the possibility and potential to become drug delivery systems that can precisely control drug release. The liquid crystallinity of lyotropic liquid crystal is a function of concentration and is mostly composed of amphiphilic molecules, the most common types being cubic, hexagonal and layered intermediate phases (Chavda et al., 2022). Many lyotropic liquid crystals have a lipid structure with similarities to the stratum corneum and strong bioadhesive properties, giving them an important place in transdermal drug delivery systems (Lotfy et al., 2022).

3.1.6 Metal-organic frameworks

Metal-organic frameworks are a class of highly ordered crystalline porous coordination polymers formed by the coordination of metal (transition metal or lanthanide metal) ions and organic ligands (carboxylates, azides, and phosphonates) that adsorb functional molecules on external surfaces or in open channels and trap these molecules in the backbone (Sun et al., 2020; Cheng et al., 2022). Metal-organic frameworks are produced by hot-melt, microwave-assisted synthesis, ultrasonic-assisted synthesis, etc. The metal-organic frameworks synthesised by different methods affect their crystal structure, size, porosity and other properties. Metal-organic frameworks can be used in conjunction with the formation of nanomaterials containing the active ingredient of a drug or with stimulus-responsive elements for the fine delivery of localised drugs (Zhao et al., 2019; Pan et al., 2022).

3.1.7 Bacteria and bacterial derivatives

Bacteria and bacterial derivatives, including bacterial ghosts and extracellular vesicles, are very promising bio-nanomaterials. Drug delivery platforms of bacteria and their derivatives retain some of the autonomous and dynamic functions of bacteria, such as colonization and targeting of human tissues, tissue penetration ability and enhanced activation of the body’s immune response (Chen et al., 2021). Compared with chemically synthesized drug carriers (nanoparticles and liposomes, etc.), drug carriers composed of natural biomaterials have both active and passive targeting properties (Cao and Liu, 2020). Endowed by means of engineering, bacteria and their derivatives can also be endowed with additional functions (Li et al., 2021).

3.1.7.1 Bacteria

Bacteria are closely associated with human health and disease development, playing a key role in preventing and maintaining atherosclerosis, fighting skin cancer, promoting skin wound healing and hair follicle rejuvenation, and neurological disorders including depression (Gilbert et al., 2013; Li et al., 2016; Naktsuji et al., 2018; Wang et al., 2021; Qiao et al., 2022). There are two common bacterial drug carriers (Li et al., 2021). One is the integration of disease-treating genes into the bacterial chromosome by means such as CRISPR-Cas9, which is developed into a living biopharmaceutical, allowing the drug to be continuously produced as the bacteria metabolize. The other is to load the drug into the living bacterial body to release the drug with bacterial lysis. Vishnu et al. studied and developed a non-pathogenic, therapeutic delivery system for Salmonella strains that can efficiently deliver bioactive proteins into cells by utilizing genetic circuits to control protein synthesis, invasion into the cell and release of protein drugs. And it can deliver drugs directly to cancer cells specifically without affecting healthy cells (Raman et al., 2021). The combination of the bacterial carrier effect with its own effects such as enhancing the immune response will certainly lead to better therapeutic results. In the future, the bacterial drug delivery system may be able to deliver drugs as precisely as an intelligent robot.

3.1.7.2 Bacterial ghosts

Bacterial ghosts are produced by the release of bacterial cytoplasmic contents through channels in the cell envelope, mainly from Gram-negative bacteria. The high number of cell wall layers, strong mechanical properties, the presence of more toxic exotoxins and the absence of a relatively simple protein secretion mechanism and high transporter capacity may be the reasons why Gram-positive bacteria are generally not used as delivery vectors but as vaccines (Hjelm et al., 2015; Wu et al., 2017). There are two methods of creating bacterial ghosts, the chemical-based “sponge-like” method and the genetically-engineered method, which is prepared by cleavage of gene E. The method is based on the use of chemical reagents. The “sponge-like” method refers to the use of chemicals to create pores through the bacterial cell wall, followed by centrifugation to remove the cell contents (Chen et al., 2021). The genetic engineering method utilizes the cleavage protein E produced by the cleavage gene E to cause the formation of transmembrane tunnels connecting the inner and outer membranes near the bacterial division site, flowing out of the cytoplasm and producing bacterial ghosts with surface structures identical to those on the surface of living cells (Ma et al., 2021). Beyond that, some bacterial ghosts have the ability to target infected macrophages (Xie et al., 2020). Combining bacterial ghosts with micro needling or subcutaneous injections would have great potential for application in bacterial infections of the skin or deep tissues.

3.1.7.3 Bacterial extracellular vesicles

Bacterial extracellular vesicles are spherical membrane particles with diameters of 20–400 nm secreted by commensal or pathogenic bacteria, which can be categorized into cytoplasmic membrane vesicles and outer membrane vesicles according to the type of bacteria secreted (Liu et al., 2022). Cytoplasmic membrane vesicles are derived from the cytoplasmic membrane of Gram-positive bacteria carrying material from the cytoplasm. Outer membrane vesicles are derived from the outer membrane of Gram-negative bacteria carrying material from periplasmic and cytoplasmic components (Toyofuku et al., 2019). Bacterial extracellular vesicles are the language of communication between bacteria and hosts, and can be used to regulate a variety of biological functions including biofilm formation, alteration of small intestinal epithelial permeability (Fizanne et al., 2023), increase in host angiogenesis and osteogenesis (Chen et al., 2022), inhibition of host viral infections and host collaboration in viral clearance (Ñahui Palomino et al., 2019; Bhar et al., 2022), induction of host resistance to other bacteria (Zhou et al., 2023), and host immunomodulation (Xie et al., 2022). Bacterial extracellular vesicles can release the contents of bacterial extracellular vesicles into host cells through three ways: endocytosis, internalization of bacterial extracellular vesicles through lipid rafts, and direct membrane fusion (Ñahui Palomino et al., 2021). Endocytosis is considered to be the main route of entry of bacterial extracellular vesicles into eukaryotic cells.

3.1.8 Cells and cell derivatives

Cells and cell derivatives, including cell membranes and cell vesicles, are drug delivery systems that modify drugs to the surface of cell membranes, encase them inside the living cell membranes, or integrate them onto cellular nucleic acids. When modified cells are delivered into a patient, such as by integrating gene fragments onto nucleic acids or wrapping around the inside of cells, they can become a kind of “living drug”, constantly producing drugs as cells metabolize or releasing a certain number of drugs as special events occur. Differences in the composition of their membranes, types of receptors, etc., of cells and cell derivatives of different origins have the ability of active/passive targeting to specific tissues. Some cells and cell derivatives also have the ability to activate the immune system, which can assist drugs to better treat diseases. Cells and cell derivatives have a wide scope for development in precision therapy and as controlled targeted drug carriers.

3.1.8.1 Cells

A cellular drug carrier is one that utilizes an intact cell or a denucleated cell as a carrier. In contrast to being intact, denuded cells not only do not proliferate or permanently engraft in the host, they also retain organelles to produce energy and proteins. Desmoplastic cells adhere to target cells or tissues through integrin-regulated adhesion and their functional properties are highly similar to those of extracellular vesicles (Wang et al., 2022). Red blood cells are unique in that they are whole cells and do not possess a nucleus of their own, allowing them to be transported to tissues through the bloodstream. Mesenchymal stem cell, with their intrinsic disease-targeting and paracrine capabilities, have gained a great deal of attention as therapeutic vectors. The short lifespan of neutrophils means that drugs can enter the bone marrow as senescent neutrophils return to the bone marrow. In addition, cells such as hematopoietic stem cells, platelets, natural killer cells, macrophages, dendritic cells, T-lymphocytes and tumor cells have also been used as drug delivery vehicles. The combination of these cells with topical implantation techniques or microneedling could have a promising future in the topical treatment of diseases of the skin and subcutaneous tissues.

3.1.8.2 Extracellular vesicles

Extracellular vesicles are nanoparticles encapsulated by lipid membranes secreted by cells, and are widely distributed in various body fluids, tissue fluids and cell culture supernatants (Hallal et al., 2022). Extracellular vesicles are both a means of disposing of harmful or unwanted intracellular components and are capable of long-range intercellular communication in vivo surface proteins, encapsulated cargo molecules (e.g., biologically bioactive molecules such as proteins, lipids, nucleic acids and sugars) (Shao et al., 2018; Buzas, 2023). Depending on the source, particle size, structure and function, extracellular vesicles can be categorized into various types such as exosomes, microvesicles, apoptotic bodies and oncosomes. The first extracellular vesicles identified were those loaded with transferrin receptors, which were excreted by reticulocytes via exosomes (Harding et al., 1984). With the exploration of extracellular vesicles, the therapeutic potential of extracellular vesicles in various diseases continues to be discovered.

3.1.8.3 Cell membrane

Cell membrane is a drug carrier in which the cell membrane of a certain cell is wrapped around the outer layer of the drug. Erythrocytes, leukocytes, platelets, cancer cells, macrophages, mesenchymal stromal cells, and exosomes have been used as cell membrane drug carriers. They closely resemble cell membrane components in vivo and carry a large number of surface molecules, possessing similar functions to cells and exosomes. Different types of cell membranes also possess their individualized functions. For example, drugs encapsulated in natural erythrocyte membranes inhibit drug uptake by the reticuloendothelial system (Rao et al., 2016). The membranes of macrophages, leukocytes and monocytes have a high affinity for inflamed and tumor-bearing regions, easily pass biological barriers, and can migrate transendothelially (Narain et al., 2017). The cell membranes of platelets have subendothelial adhesion properties as well as the ability to interact with pathogens (Kunde and Wairkar, 2021). Human keratinocyte membranes can achieve precise targeted release of drugs in the skin, which has a broad application prospect in dermatological treatment and functional cosmetic delivery (Jing et al., 2021).

3.1.9 Inorganic drug carriers

Drug carriers made from organic materials can easily dissolve and encapsulate poorly water-soluble drugs into their hydrophobic cores, but are also physicochemically and chemically unstable, making them susceptible to accidental drug leakage. Drug carriers made from inorganic materials such as mesoporous silica nanoparticles, carbon nanomaterials and gold nanoparticles are highly physicochemically and biochemically stable, less expensive to manufacture, and can provide sufficient attachment sites for a variety of organic components. Many inorganic drug carriers can also be prepared in a variety of sizes, structures and geometries. Compared to some highly biocompatible organic carriers, inorganic carriers are less able to cross the skin barrier, but the high drug loading capacity can be used as a strategy to control the retention and release of therapeutic candidates.

3.1.9.1 Silicon dioxide

Silicon dioxide drug carriers are drug carriers made of silicon dioxide, first synthesised in the 1990s, and are available in spherical, rod and flake shapes (Vallet-Regí et al., 2022). A type of silica porous microspheres with pore sizes ranging from 2 to 50 nm has occupied an important position in the family of silica drug carriers since its discovery, which is mesoporous silica (Vallet-Regí et al., 2022). In addition to this, many researchers have structurally modified mesoporous silica to give mesoporous silica a richer and more personalized advantage. For example, Xu et al. utilized a chiral amide gel-directed synthesis method that could give mesoporous silica significant chiral activity (Xu et al., 2023). Shiekh et al. modified mesoporous silica with hexamethylsilazane, which avoided agglomeration and was more conducive to targeted delivery (Shiekh et al., 2022). Difficulty in entering the bloodstream through the human stratum corneum even with the addition of chemical penetrating agents is the main obstacle that restricts the use of mesoporous silica drug carriers for some topical drugs. However, Zhao et al. utilized the drag effect of low eutectic solvents to enable mesoporous silica drug carriers to effectively penetrate the entire skin (Zhao et al., 2022).

3.1.9.2 Calcium carbonate

Calcium carbonate is one of the most widespread minerals found in nature and is also widely found in living organisms as a structural support. Calcium carbonate exists in various forms, such as amorphous and crystalline. There are six known crystalline forms of calcium carbonate, namely, calcite, aragonite, spherulite, calcium carbonate monohydrate, calcium carbonate hexahydrate, and calcium carbonate hemihydrate. The Ca^2+- CO₃^2- reaction system is the most commonly used way to synthesize calcium carbonate. Calcium carbonate with different sizes, morphologies and crystalline forms can be obtained by changing the reaction conditions (Niu et al., 2022). Surface modification is the main method to expand the application of calcium carbonate in drug carriers. Calcium carbonate was further engineered into porous, hollow or core-shell organic-inorganic nanocomposites by organic modification or inorganic modification, followed by template-induced biomineralization and layer-by-layer assembly of the resulting CaCO₃ (Niu et al., 2022). Dong et al. utilized hollow calcium carbonate-polydopamine composite nanomaterials to fabricate a photosensitizer-loaded drug carrier that could significantly reduce phototoxicity and thus effectively minimize skin damage during in vivo antitumor photodynamic therapy (Dong et al., 2018).

3.2 Drug-smart response element

Drug-smart response elements are elements that can be targeted for delivery to a focal site after receiving a specific external or internal stimulus. In contrast to conventional drugs, stimuli-responsive elements can use a variety of principles to respond to subtle changes in the body’s environment, thereby delivering the drug precisely to the target site, which can reduce unwanted toxic side effects of the drug at non-target sites without increasing the concentration of the drug (Table 4).

TABLE 4

TABLE 4. Classification, advantages, disadvantages and applications of drug-smart response elements.

3.2.1 Ligand-mediated of drug-smart response element

Chemical modification has been an important way to improve the performance of drugs or carriers. Ligand-drug couplings are one such chemical modification method that has received widespread attention, first appearing in the 1870s (Chau et al., 2019). Small molecules have since been used as ligands, but antibodies as ligands have been the most dominant research direction. Currently, antibody couplings are developing rapidly. In addition to enhancing the targeting ability of drugs, antibody couplers can also activate the body’s immune response and regulate cell behaviour (Qian et al., 2021; Liu et al., 2023). The choice of antibodies is not limited to proteins with direct potency similar to those in the human body, but also includes bacterial surface proteins with indirect potency (Lahav-Mankovski et al., 2020). Some researchers have found that further modification of bacterial antibodies can give bacteria programmable properties to more finely regulate the organism by inducing cellular functions in a manner similar to cell surface protein responses. However, antibody couplings have a poor ability to penetrate barriers, and intravenous injection is the predominant route of administration. The application of microneedling and embedding technologies may be an important step in further expanding the application of ligand-mediated drug smart response elements.

3.2.2 pH-responsive drug smart response element

pH-Responsive drug smart response element is a drug delivery system that combines a pH-responsive structure, such as a 3+ carboxylic acid ligand, through surface adsorption, surface modification and mixing (Guillen et al., 2022; Tian et al., 2022). The most commonly used design is the modification of the carboxyl group of a protein with a stilbene analogue, which binds to the biologically active ingredient of a target drug having p-dimethylaminobenzaldehyde or to a drug carrier (Herold et al., 2020). pH-responsive drug smart response elements allow for the slow, sustained release of drugs from the smart response element at varying rates depending on the acidification conditions of the human environment, and have great potential for the long-term sustained release of drugs. In vivo pH-responsive drug smart response elements have major limitations. However, pH-responsive drug smart response elements have great applications in skin bacterial infections and trauma (Xie et al., 2023).

3.2.3 Redox-responsive drug smart response element

Redox-responsive drug-smart response elements typically contain disulfide and diselenide bonds that load the active pharmaceutical ingredient in a covalent or non-covalent manner and release the active pharmaceutical ingredient in response to oxidative stimulation (Li et al., 2022). The most commonly recognized substrates are reactive oxygen species and glutathione. The very slow kinetics of the classical “thiol-disulfide bond exchange reaction” is a major drawback of redox-responsive drug-smart response elements. Relief through the addition of core gating molecules can improve the accuracy of drug release and enable more precise disease targeting (Li et al., 2022). Because bacteria contain high concentrations of glutathione, the redox-responsive drug smart response element is likely to clear the bacteria (Wu et al., 2023). The skin is more prone to artificially modulate drugs, and redox-responsive drug-smart response elements have great potential for skin or mucosal antimicrobials.

3.2.4 Enzyme-responsive drug smart response element

The design principle of enzyme-responsive drug smart response elements is to utilize specific interactions between enzymes and substrates to prepare drug-smart response elements that can be specifically degraded by specific enzymes (Zhou et al., 2022). Precise localisation of enzyme-drug smart response elements could control the drug release dose according to disease severity and greatly reduce cytotoxicity (Zuo et al., 2020; Chen et al., 2021). In addition to this, enzyme-drug smart response elements have some personalized advantages. Self-assembled peptide thioesters consisting of aminoethyl thioesters as substrates for thioesterases can act on the Golgi apparatus of target cells in a timely and efficient manner via an enzymatic reaction, leading to cell death through a variety of pathways (Tan et al., 2022). Enzyme-responsive drug smart response elements can deliver live drugs such as cells and bacteria. Yang et al. solved the problems of low cell survival and severe immune rejection by utilizing matrix metalloproteinase-7-responsive nanoshells to encapsulate HeLa cells and human mesenchymal stem cells (Yang et al., 2019).

3.2.5 Magnetically responsive drug smart response element

Magnetic nanoparticles are 10–100 nanoparticles represented by iron, cobalt, nickel or metal oxides with inherent magnetic properties are the main source of magnetically responsive targeted drug delivery systems (Shi et al., 2022). Superparamagnetic magnetic hematite (γ-Fe2O3) or magnetite (Fe₃O₄) are commonly used magnetic nanoparticles in magnetically responsive drug smart response elements. Micro-robotics is the most ideal development direction for magnetically responsive drug smart response elements. An ideal micro-robotic drug smart response element should fulfill four core requirements: 1) high loading capacity, 2) protection of the drug from the external environment, 3) controllable propulsion mechanism, and 4) on-demand drug release (Song et al., 2022). However, achieving the above conditions using magnetically responsive elements is a long way from controlling the micro-robot to deliver the drug to the specified location.

3.3 Factors affecting transdermal drug absorption

Permeation of drugs through biological or synthetic membranes occurs through three main modes of transport: passive, active or facile. Transdermal absorption in humans or animals is the passive diffusion of drugs from carriers or excipients on skin surface tissues to reach the systemic circulation (Schaefer et al., 2013). The physiologic structures involved in the transdermal absorption of topical medications are the stratum corneum, hair follicles, sebaceous glands, and sweat duct orifices. The pathways of topical drug penetration through the stratum corneum can be categorized into three: 1) Intercellular pathway: chemicals bypass the keratinocytes and penetrate into the subcutis through the intercellular matrix that is continuously distributed between the keratinocytes (Barbero and Frasch, 2006). This is the main route for bioactive composition in drugs with very small molecular weights to enter the skin. The bioactive components of drugs that enter the skin via the intercellular route are of low molecular weight and have a certain degree of lipid- and water-solubility (David, 2014). 2) Transcellular entry: the chemical enters the target site either directly through keratinocytes and mesenchyme or through efflux and uptake transporters using transporters (Haque and Talukder, 2018; Bajza et al., 2020). The bioactive composition with smaller molecular weights directly pass through the cell membrane, while the components with larger molecular weights interact with transport proteins and pass through the cell membrane through efflux and uptake transporters (Idson, 1975). 3) The transdermal route by which chemicals enter the dermis directly through skin appendages such as hair follicles, sebaceous glands and sweat duct orifices is also known as the bypass route. In most cases, drug bioactive composition with large molecular weights or peculiar structures have difficulty in passing through the thicker lipid-rich stratum corneum and enter the skin mainly via the bypass route (Stoughton, 1965). The total area of the skin appendages is relatively small, but it has a significant impact on the skin permeability of drug bioactive composition (Marwah et al., 2016). The bypass pathway is an important reason why topical drugs resemble slow-release drugs. The storage of drugs in the skin appendages and the extremely thin stratum corneum of the skin appendages allow large molecular weight drug bioactive composition to cross the skin slowly at a constant rate for a certain period of time to reach the target site (Scheuplein and Blank, 1971; Ishii et al., 2010).

The nature of drug absorption on the skin is a passive diffusion process from the outer part of the skin, where the concentration is high, to the inner regions of the skin, where the concentration is low. In principle, all three pathways follow Fick’s law of diffusion, which states that the flux or motion of a molecule diffusing across a membrane is proportional to the difference in concentration of that molecule on either side of the membrane (Idson, 1975). The formula based on Fick’s first law of diffusion indicates that the maximum flux of a drug is proportional to the difference in skin concentration and inversely proportional to the thickness of the stratum corneum. Fick’s second law of diffusion suggests that the relationship between diffusion distance and the duration until an isopore (an area of the same drug concentration) is reached is not linear, but increases disproportionately with increasing diffusion distance (Wohlrab and Eichner, 2023). However, the efficacy of some drugs decreases significantly with increasing drug concentration (Hemmati et al., 2011), indicating that in addition, there are other important factors that similarly influence drug penetration and absorption. The integrity and properties of the membrane (skin) as the main body for the penetration of the bioactive composition of the drug have a great influence on the penetration of the drug (Gattu and Maibach, 2011). Lipid-water partition coefficients, solubility, melting point, molecular size and shape are widely recognized as important physicochemical factors that influence skin penetration and absorption of drug bioactive composition by their own properties. The strength of the effect of different factors on the penetration of bioactive composition of drugs is closely related to the structural composition of the skin and the prevailing skin condition (Lien and Tong, 1973; Michaels et al., 1975; Roberts et al., 1977). Magnusson et al. found that epidermal permeability coefficient and solute octanol-water partition coefficient were the key factors in the permeation efficiency of pharmaceutical bioactive composition (Magnusson et al., 2004). Molecular weight is an important factor in determining the maximum permeation flux of a pharmaceutical bioactive compound. The permeation of pharmaceutical bioactive compounds is also related to the specific surface area of the particles, the diffusion coefficient of the solute, the thickness of the boundary layer and the solubility of the solute (Sandri et al., 2014). The rate of permeation of a solute from an aqueous solution depends on the efficiency of partitioning and diffusion. The efficiency of solute partitioning in solution is related to the octanol-water partition coefficient. The efficiency of solute partitioning in solution is related to solute size and hydrogen bonding (Zhang et al., 2009). Passive diffusion of drugs through the skin is influenced by the physicochemical properties of the drug bioactive composition and by individualized differences in the structure and physiological state of the skin. However, not all drug bioactive composition penetrates at a higher rate in damaged skin than in normal skin. For example, nicotine transmits at a higher rate through normal healthy skin than through skin previously damaged by corrosive or destructive chemicals or physical agents (e.g., heat and cold) (Macht, 1938). Hydration not only plays an important role in skin barrier function, but also plays a major role in promoting the absorption of drug bioactive composition. Hydration of the stratum corneum can lead to profound changes in skin barrier properties. In its normal state, the stratum corneum contains 15%–20% water, and stratum corneum water can increase to about 400% after over-soaking (Dawber, 1980). Upon absorption by keratinocytes, water alters the position and stability of the disulfide bonds in keratin peptides, causing changes in the spatial orientation of the protein (Walters, 2002). The change in the spatial orientation of the proteins gives more space to the water molecules, allowing the water content of the keratinocytes to increase further. When the keratinocytes themselves swell, the denseness of the structure decreases, the cellular gap between the keratinocytes widens, and the permeability of the skin increases. The hydration of the skin can change the physicochemical properties of the bioactive composition of the drug and increase the diffusion coefficient of the bioactive composition of the drug. As the water content of the keratinocytes increases, the bioactive composition of the drug are more likely to combine with water to form hydrated molecules (Scheuplein et al., 1969; Wiedmann, 1988). In addition to this, pH and temperature also affect the transdermal absorption of drugs. pH is not absolute in its effect on the transdermal absorption of the bioactive composition of a drug. For example, the transdermal absorption dose of indomethacin increases as the pH of the skin surface decreases, a pattern that is not necessarily true for other pharmaceutical bioactive composition (Chiang et al., 1991). Alteration of pH affects the ionization of drug bioactive composition may be the main reason why pH affects the transdermal absorption of drug bioactive composition. Unlike pH, an increase in temperature generally increases the transdermal absorption of drug bioactive composition. Temperature increases skin blood flow at the site of heat application mainly by promoting skin vasodilation, which significantly increases the rate of transdermal absorption of drugs and the dose of transdermal absorption (Barkve et al., 1986; Hao et al., 2016).

4 Individualized drug use that affects the effectiveness of individualized dosing

The effect of the same drug on different individuals can vary greatly. The main reasons for this difference are family heredity, disease, age, weight and the concurrent use of other drugs. Personalized medicine refers to the formulation of a more reasonable treatment plan with full consideration of each patient’s individual situation. Thus, improving the efficacy of drugs, reducing the side effects of drugs in a more economical way achieve better therapeutic effect.

4.1 Pharmacogenomics affecting the effectiveness of individualized dosing

As everyone knows genetic sequence varies from person to person by only one in a thousand. Deletion, insertion, duplication and inversion are the four genetic structural variants that are always present. Metabolic enzyme, transporter, receptor and other genes encoding metabolic enzyme regulate the absorption, distribution, metabolism and excretion of substances in the human body. This makes the same concentration of the drug have different therapeutic effects and adverse effects on people with different genotypes. Large studies have shown that adverse drug reactions occurring in hospitals are one of the leading causes of death among American hospital patients (Roden et al., 2019). 97%–98% have at least one functional drug-related gene variant (Schärfe et al., 2017). These studies have shown that exploring human drug-related genes is particularly important for individualising medication and improving drug efficacy, hence the emergence of pharmacogenomics. Metoprolol is an important drug in the treatment of various cardiovascular diseases, thyroid crisis and localised choroidal haemangiomas (Zamir et al., 2022). The metabolism of the polymorphic enzyme CYP2D6 is the main reason that affects the metabolic rate of Metoprolol in vivo. In one study, the genotypes of patients were 30% extensive metabolizers, 55% intermediate metabolizers, and 13% weak metabolizers (Anstensrud et al., 2020). If the same drug dose is used in people with the CYP2D6 weak metabolism genotype, the risk of adverse reactions during Metoprolol treatment is 5 times higher than in people with the non-weak metabolism genotype (Bijl et al., 2009). Adjusting Metoprolol dosage according to genotype significantly reduces the probability and severity of adverse reactions in patients. More and more genotypic and phenotypic information related to the pharmacogenome is being discovered and many very useful databases have been established. As of April 2021, PharmGKB contains 715 drugs 1761 genes, 227 diseases, 165 clinical guidelines, and 784 drug labels (Gong et al., 2021). In PharmGKB, we have access to genotypic and phenotypic information related to the pharmacogenome. It includes drug dosing guidelines, drug labelling annotations, clinical and variant annotations, summary of drug-centred pathways, pharmacodynamic genes and the relationship between genes, drugs and disease. Approximately 4/5 patients may carry a variant that is a target for commonly prescribed drugs and may also have a functional impact, a variant that may alter drug efficacy (Schärfe et al., 2017). The correct use of gene sequencing tools and pharmacogenomics-related databases can effectively guide patients in the rational use of medication, improve drug effectiveness and reduce adverse drug reactions.

4.2 Microbiomes influencing the effectiveness of individualized dosing

The human organism contains hundreds of microorganisms with different biochemical functions that are relevant to human life. In recent decades, researchers have discovered that microorganisms also play a role in drug metabolism and efficacy. Zimmermann et al. analyzed 76 bacterial species, metabolizing 271 oral drugs in vitro and found that at least one strain was able to metabolize 2/3 of the drug (Zimmermann et al., 2019). Chemical modification of microorganisms is an important cause of altered drug efficacy. 5-aminosalicylic acid has a significant inhibitory effect on intestinal wall inflammation (Tavares Junior et al., 2022). With increased use, resistance develops in most patients. Anaerobic faecal culture experiments have shown that up to one-third of 5-aminosalicylic acid is metabolised by microorganisms to a form that lacks anti-inflammatory activity, N-acetyl-5-aminosalicylic acid (Dull et al., 1987). Mehta et al. identified 12 previously uncharacterized enzyme genes associated with 5-aminosalicylic acid inactivation and found that an increase in the number of these enzyme genes correlated with steroid use (Mehta et al., 2023). Metabolites of microorganisms can also affect the efficacy of drugs. Koh et al. found higher levels of imidazolepropionic acid, a metabolite of the gut flora, in patients who were not well treated with metformin (Koh et al., 2020). Further studies showed that imidazole propionate inhibited metformin-induced adenosine 5′-monophosphate-activated protein kinase activation via p38g and Akt, whereas pirfenidone blocked p38γ activation by imidazole propionate and restored the hypoglycaemic effect of metformin inhibited by imidazole propionate. Metabolism of drugs by microorganisms is the source of some adverse drug reactions. Clonazepam is an antiepilepsy and anxiolytic drug, and the breakdown product of this drug, vinylpyrimidine bromide, is severely toxic. Zimmermann et al. found that the serum level of bromoacetyluracil was five times higher in normal mice than in germ-free mice after the use of clonazepam (Zimmermann et al., 2019). The microbiome is relatively new and many of the current studies do not directly benefit patients, but there is no doubt that microbial metabolism has a huge impact on drug metabolism and efficacy. Moreover, the current microbiome research mainly focuses on the intestinal flora, and the research on skin microorganisms is relatively backward, which is not conducive to the research on the individualization of topical medications. Analyzing the reasons why drugs are metabolized by microorganisms can link individual differences in the microbiome to individual differences in drug metabolism, which can be targeted to accurately guide patients in the rational use of medication by restoring the efficacy of the drug or reducing the adverse effects of the drug.

4.3 Artificial intelligence modelling of the effectiveness of individualized dosing

Over the past decade, artificial intelligence (AI) has undergone a revolution that is bound to transform economics, society and science, solving many seemingly intractable problems (Richards et al., 2022). In the field of pharmaceuticals, AI has achieved excellent results in data processing, drug discovery (Schneider et al., 2020), image processing (Bera et al., 2021), and chemical structure analysis (Bojar and Lisacek, 2022). However, due to reasons such as medical datasets being difficult to access and the medical field being too large and complex. AI has not really made a real difference in the medical field. As it stands, assisting in disease identification and classification is one of the most promising aspects of AI. Accurate disease delineation and documentation can assist us in identifying and addressing more subtypes of disease further enabling individualized drug delivery. In this context, Acosta proposed a multimodal medical AI model that processes multiple types of information (Acosta et al., 2022). In this model, the AI model is able to make good use of data from both clinical and non-clinical databases, thus truly enabling AI to diagnose and treat diseases. Moor proposed another new paradigm of medical AI (Moor et al., 2023), known as the model of holistic medical AI. This model labelled data, flexibly interpreting data from different combinations of medical patterns and producing expressive outputs through self-supervision of large, diverse datasets. The models of omnipotent medical AI have the ability to customize queries to interact with the model compared to multimodal medical AI models, flexible combinations of different data modalities can be received and results output, allowing inference using undirected tasks. Multimodal medical AI models and all-round medical AI models require a diverse and specialized large database, which is very difficult and requires a very large financial investment. The processing of high-throughput data and the high accuracy requirements of models are also important issues that cannot be ignored in both types of modelling. AI is generally superior to individual physicians in data processing, and it can perform more complex information processing, find new subtypes of disease, and discover links between an individual’s characteristics and medication use, leading to better and more precise selection of medication types and dosages for an individual, and thus improving medication efficacy.

5 Conclusion and outlook

More than half of the world’s population uses at least one drug per day, and as the global burden of disease continues to grow, the demand for drugs will continue to increase (Baryakova et al., 2023). Patient compliance is an important factor in disease treatment. Statistically, poor adherence leads to 10% of hospitalizations, resulting in $100 - $300 billion in avoidable healthcare costs and causing approximately 125,000 U.S. patient deaths annually (Baryakova et al., 2023). Oral medication is the most common and highest patient compliance route of medication use. However, most oral medications are not specific and may cause side effects. Metabolism in the gastrointestinal tract and liver can further reduce the dose of bioactive ingredients reaching the target site. Topical administration is a promising and effective method of drug delivery. Topical medication is a highly compliant mode of administration, is not metabolised in the gastrointestinal tract and has a high specificity for skin tissues.

Dermatological diseases are the greatest advantage of topical medication. Topical drugs can quickly reach the target site of skin diseases, shorten the time for the drug to produce therapeutic effects, and avoid the adverse effects of drug hoarding in other tissues. The skin is a complex and sophisticated tissue composed of microorganisms that inhabit the surface layer, cells that make up the structure of the skin, immune cells and their metabolites that are involved in innate immunity, adaptive immunity, and that help to protect the organism against external aggressions, guaranteeing the organism’s ability to survive in a harsh and dry external environment. The effectiveness of topical treatments is influenced by a number of factors. The transport of the bioactive composition of a topical drug from the skin to the target site is a key step in the efficacy of topical drugs. Regardless of the target site of the disease, the bioactive composition of topical drugs needs to cross the stratum corneum barrier. Dermatological diseases in which the bioactive composition crosses the stratum corneum barrier and reaches the target site directly to take effect. In subcutaneous tissue diseases, the bioactive composition has to be further diffused and cleared by metabolism and dermal circulation to reach deeper tissues. In diseases of other tissues and organs, bioactive composition also needs to be transported through the bloodstream to reach the target site. Enabling drug penetration through the skin is a major concern for topical drug delivery. The state of the skin barrier, the physicochemical properties of the bioactive composition, the excipients and additives of the agent, the drug delivery system and external means of altering the efficiency of transdermal absorption, such as heat and iontophoresis, all affect the efficiency and dose of the bioactive composition in reaching the target site, and thus the effectiveness of the bioactive composition. Undeniably, the question of how to enhance the transdermal absorption of drugs into the skin is a very important one. The advent of drugs of enormous size, such as proteins, nucleic acids and bacteria, has led to a demand for methods to increase the transdermal absorption of drugs. However, enhancing transdermal absorption of drugs is not the first option to improve the effectiveness of all drugs. Drugs with small molecule compounds as the main bioactive composition are still the most commonly used topical drugs in the clinic. Small molecule actives usually have a very good ability to penetrate the skin. Excessive promotion of transdermal absorption of drugs containing small molecules of biologically active ingredients results in most of the biologically active ingredient entering the bloodstream, while less of the drug is available at the target site of the skin, thus reducing the efficacy of the treatment. If the frequency of use of small molecules is increased, there is a high likelihood of causing adverse reactions in other tissues. Thus, it appears that small molecule topical drugs have a greater need to limit the rate of transdermal absorption. Mineral-based materials, such as apatite, diamond and montmorillonite clay, are currently important in limiting the transdermal penetration of bioactive composition of drugs and maintaining local action (Choimet et al., 2020; Shapira et al., 2022; Wang and Phillips, 2022). However, there are fewer studies of mineral-based materials in topical drug delivery systems, and the mechanism of action is unclear. Research on mineral-based materials as topical drug carriers is a blue ocean and more researchers need to participate in it.

Topical pharmaceutical preparations are emerging as an attractive alternative and a rapidly growing market. A variety of factors can influence the final efficacy. No one topical drug or topical drug delivery system is right for everyone. Individualized medication is an important way to improve the effectiveness of drug use. Individualized precision medication administration also achieves optimal outcomes for patients in a more cost-effective manner and reduces unnecessary capital expenditure. However, the complexity of influencing factors and mechanisms of action yet to be fully explored limit the practical application of precise individual administration of topical drugs. Continuing developments in pharmacogenomics, microbiomics and artificial intelligence modelling are continuing to fill the gaps in theoretical research. However, there is still a long way to go for the application of precise individual medication, and it still requires the continuous joint efforts of all parties.

Author contributions

LZ: Writing–original draft. JC: Writing–original draft. BB: Writing–original draft. GS: Writing–original draft. JZ: Writing–review and editing. HY: Writing–review and editing. SH: Writing–review and editing. ZW: Conceptualization, Supervision, Writing–review and editing. GL: Conceptualization, Supervision, Writing–review and editing.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors gratefully acknowledge the financial support from Sichuan Provincial Drug Administration Chinese Medicine (Ethnomedicine) Standard Enhancement Project (Second) (No. 510201201904914).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Acosta, J. N., Falcone, G. J., Rajpurkar, P., and Topol, E. J. (2022). Multimodal biomedical AI. Nat. Med. 28 (9), 1773–1784. doi:10.1038/s41591-022-01981-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Alicea, G. M., Rebecca, V. W., Goldman, A. R., Fane, M. E., Douglass, S. M., Behera, R., et al. (2020). Changes in aged fibroblast lipid metabolism induce age-dependent melanoma cell resistance to targeted therapy via the fatty acid transporter FATP2. Cancer Discov. 10 (9), 1282–1295. doi:10.1158/2159-8290.cd-20-0329

PubMed Abstract | CrossRef Full Text | Google Scholar

An, Y., Zhu, J., Liu, F., Deng, J., Meng, X., Liu, G., et al. (2019). Boosting the ferroptotic antitumor efficacy via site-specific amplification of tailored lipid peroxidation. ACS Appl. Mater. interfaces 11 (33), 29655–29666. doi:10.1021/acsami.9b10954

PubMed Abstract | CrossRef Full Text | Google Scholar

Anderson, N. R., Minutolo, N. G., Gill, S., and Klichinsky, M. (2021). Macrophage-based approaches for cancer immunotherapy. Cancer Res. 81 (5), 1201–1208. doi:10.1158/0008-5472.CAN-20-2990

PubMed Abstract | CrossRef Full Text | Google Scholar

Anstensrud, A. K., Molden, E., Haug, H. J., Qazi, R., Muriq, H., Fosshaug, L. E., et al. (2020). Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction – a prospective observational study. Eur. J. Clin. Pharmacol. 76 (5), 673–683. doi:10.1007/s00228-020-02832-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Bajza, Á., Kocsis, D., Berezvai, O., Laki, A. J., Lukács, B., Imre, T., et al. (2020). Verification of P-glycoprotein function at the dermal barrier in diffusion cells and dynamic "Skin-On-A-Chip" microfluidic device. Pharmaceutics 12 (9), 804. doi:10.3390/pharmaceutics12090804

PubMed Abstract | CrossRef Full Text | Google Scholar

Barbero, A. M., and Frasch, H. F. (2006). Transcellular route of diffusion through stratum corneum: results from finite element models. J. Pharm. Sci. 95 (10), 2186–2194. doi:10.1002/jps.20695

PubMed Abstract | CrossRef Full Text | Google Scholar

Barkve, T. F., Langseth-Manrique, K., Bredesen, J. E., and Gjesdal, K. (1986). Increased uptake of transdermal glyceryl trinitrate during physical exercise and during high ambient temperature. Am. heart J. 112 (3), 537–541. doi:10.1016/0002-8703(86)90518-1

PubMed Abstract | CrossRef Full Text | Google Scholar

Baroni, A., Buommino, E., De Gregorio, V., Ruocco, E., Ruocco, V., and Wolf, R. (2012). Structure and function of the epidermis related to barrier properties. Clin. dermatology 30 (3), 257–262. doi:10.1016/j.clindermatol.2011.08.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Barrera, J. B., Gijsen, H., González, A., De Groot, A., Prota, G., Wijnberg, J., et al. (1995). The chemistry of melanins and melanogenesis. Fortschritte der chemie organischer naturstoffe/progress Chem. Org. Nat. Prod. 64, 93–148. doi:10.1007/978-3-7091-9337-2_2

PubMed Abstract | CrossRef Full Text | Google Scholar

Baryakova, T. H., Pogostin, B. H., Langer, R., and McHugh, K. J. (2023). Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems. Nat. Rev. Drug Discov. 22 (5), 387–409. doi:10.1038/s41573-023-00670-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Bera, K., Braman, N., Gupta, A., Velcheti, V., and Madabhushi, A. (2021). Predicting cancer outcomes with radiomics and artificial intelligence in radiology. Nat. Rev. Clin. Oncol. 19 (2), 132–146. doi:10.1038/s41571-021-00560-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Bhar, S., Zhao, G., Bartel, J. D., Sterchele, H., Del Mazo, A., Emerson, L. E., et al. (2022a). Bacterial extracellular vesicles control murine norovirus infection through modulation of antiviral immune responses. Front. Immunol. 13, 909949. doi:10.3389/fimmu.2022.909949

PubMed Abstract | CrossRef Full Text | Google Scholar

Bhardwaj, N., and Kundu, S. C. (2010). Electrospinning: a fascinating fiber fabrication technique. Biotechnol. Adv. 28 (3), 325–347. doi:10.1016/j.biotechadv.2010.01.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Bhuptani, R. S., and Patravale, V. B. (2019). Starch microsponges for enhanced retention and efficacy of topical sunscreen. Mater. Sci. Eng. C, Mater. Biol. Appl. 104, 109882. doi:10.1016/j.msec.2019.109882

PubMed Abstract | CrossRef Full Text | Google Scholar

Bielecki, P., Riesenfeld, S. J., Hütter, J. C., Torlai Triglia, E., Kowalczyk, M. S., Ricardo-Gonzalez, R. R., et al. (2021a). Skin-resident innate lymphoid cells converge on a pathogenic effector state. Nature 592 (7852), 128–132. doi:10.1038/s41586-021-03188-w

PubMed Abstract | CrossRef Full Text | Google Scholar

Bijl, M. J., Visser, L. E., van Schaik, R. H., Kors, J. A., Witteman, J. C., Hofman, A., et al. (2009). Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin. Pharmacol. Ther. 85 (1), 45–50. doi:10.1038/clpt.2008.172

PubMed Abstract | CrossRef Full Text | Google Scholar

Bode, S. A., and Löwik, D. W. P. M. (2017). Constrained cell penetrating peptides. Drug Discov. today. Technol. 26, 33–42. doi:10.1016/j.ddtec.2017.11.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Bojar, D., and Lisacek, F. (2022). Glycoinformatics in the artificial intelligence era. Chem. Rev. 122 (20), 15971–15988. doi:10.1021/acs.chemrev.2c00110

PubMed Abstract | CrossRef Full Text | Google Scholar

Boscariol, R., Caetano, É. A., Silva, E. C., Oliveira, T. J., Rosa-Castro, R. M., Vila, M. M. D. C., et al. (2021). Performance of choline geranate deep eutectic solvent as transdermal permeation enhancer: an in vitro skin histological study. Pharmaceutics 13 (4), 540. doi:10.3390/pharmaceutics13040540

PubMed Abstract | CrossRef Full Text | Google Scholar

Bui, V. D., Son, S., Xavier, W., Nguyen, V. Q., Jung, J. M., Lee, J., et al. (2022). Dissolving microneedles for long-term storage and transdermal delivery of extracellular vesicles. Biomaterials 287, 121644. doi:10.1016/j.biomaterials.2022.121644

PubMed Abstract | CrossRef Full Text | Google Scholar

Buzas, E. I. (2023). The roles of extracellular vesicles in the immune system. Nat. Rev. Immunol. 23 (4), 236–250. doi:10.1038/s41577-022-00763-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Byrd, A. S., Carmona-Rivera, C., O'Neil, L. J., Carlucci, P. M., Cisar, C., Rosenberg, A. Z., et al. (2019). Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa. Sci. Transl. Med. 11 (508), eaav5908. doi:10.1126/scitranslmed.aav5908

PubMed Abstract | CrossRef Full Text | Google Scholar

Cao, H., Gao, Y., Jia, H., Zhang, L., Liu, J., Mu, G., et al. (2022a). Macrophage-membrane-Camouflaged nonviral gene vectors for the treatment of multidrug-resistant bacterial sepsis. Nano Lett. 22 (19), 7882–7891. doi:10.1021/acs.nanolett.2c02560

PubMed Abstract | CrossRef Full Text | Google Scholar

Cao, Z., and Liu, J. (2020). Bacteria and bacterial derivatives as drug carriers for cancer therapy. J. Control. release official J. Control. Release Soc. 326, 396–407. doi:10.1016/j.jconrel.2020.07.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Chang, Y., Cai, X., Syahirah, R., Yao, Y., Xu, Y., Jin, G., et al. (2023). CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy. Nat. Commun. 14 (1), 2266. doi:10.1038/s41467-023-37872-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Chau, C. H., Steeg, P. S., and Figg, W. D. (2019). Antibody-drug conjugates for cancer. Lancet (London, Engl. 394 (10200), 793–804. doi:10.1016/s0140-6736(19)31774-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Chavda, V. P., Dawre, S., Pandya, A., Vora, L. K., Modh, D. H., Shah, V., et al. (2022). Lyotropic liquid crystals for parenteral drug delivery. J. Control. release official J. Control. Release Soc. 349, 533–549. doi:10.1016/j.jconrel.2022.06.062

CrossRef Full Text | Google Scholar

Chavda, V. P., Dyawanapelly, S., Dawre, S., Ferreira-Faria, I., Bezbaruah, R., Rani Gogoi, N., et al. (2023). Lyotropic liquid crystalline phases: drug delivery and biomedical applications. Int. J. Pharm. 647, 123546. doi:10.1016/j.ijpharm.2023.123546

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, C. Y., Rao, S. S., Yue, T., Tan, Y. J., Yin, H., Chen, L. J., et al. (2022a). Glucocorticoid-induced loss of beneficial gut bacterial extracellular vesicles is associated with the pathogenesis of osteonecrosis. Sci. Adv. 8 (15), eabg8335. doi:10.1126/sciadv.abg8335

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, H., Ji, H., Kong, X., Lei, P., Yang, Q., Wu, W., et al. (2021b). Bacterial ghosts-based vaccine and drug delivery systems. Pharmaceutics 13 (11), 1892. doi:10.3390/pharmaceutics13111892

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, L., Yan, D., Wu, N., Yao, Q., Sun, H., Pang, Y., et al. (2021a). Injectable bio-responsive hydrogel for therapy of inflammation related eyelid diseases. Bioact. Mater. 6 (10), 3062–3073. doi:10.1016/j.bioactmat.2021.02.040

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, L., Zhou, Z., Hu, C., Maitz, M. F., Yang, L., Luo, R., et al. (2022b). Platelet membrane-coated nanocarriers targeting plaques to deliver anti-CD47 antibody for atherosclerotic therapy. Res. Wash. D.C.) 2022, 9845459. doi:10.34133/2022/9845459

CrossRef Full Text | Google Scholar

Chen, S. (2016). The external treatment theory and Application about "Yellow Emperor's Inner Canon" bachelor's degree. China: Liaoning University of Traditional Chinese Medicine.

Google Scholar

Chen, Y. E., Fischbach, M. A., and Belkaid, Y. (2018). Skin microbiota-host interactions. Nature 553 (7689), 427–436. doi:10.1038/nature25177

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheng, R., Jiang, L., Gao, H., Liu, Z., Mäkilä, E., Wang, S., et al. (2022). A pH-responsive cluster metal-organic framework nanoparticle for enhanced tumor accumulation and antitumor effect. Adv. Mater. Deerf. Beach, Fla.) 34 (42), e2203915. doi:10.1002/adma.202203915

CrossRef Full Text | Google Scholar

Chiang, C. H., Lai, J. S., and Yang, K. H. (1991). The effects of pH and chemical enhancers on the percutaneous absorption of indomethacin. Drug Dev. industrial Pharm. 17, 91–111. doi:10.3109/03639049109043812

CrossRef Full Text | Google Scholar

Chieosilapatham, P., Kiatsurayanon, C., Umehara, Y., Trujillo-Paez, J. V., Peng, G., Yue, H., et al. (2021). Keratinocytes: innate immune cells in atopic dermatitis. Clin. Exp. Immunol. 204 (3), 296–309. doi:10.1111/cei.13575

PubMed Abstract | CrossRef Full Text | Google Scholar

Choi, D., Kim, H., Kim, D., Heo, J., Lee, H., Lee, J. B., et al. (2019). Self-assembled DNA hollow spheres from microsponges. Biofabrication 11 (2), 025016. doi:10.1088/1758-5090/ab0abb

PubMed Abstract | CrossRef Full Text | Google Scholar

Choi, Y. R., Collins, K. H., Springer, L. E., Pferdehirt, L., Ross, A. K., Wu, C. L., et al. (2021). A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery. Sci. Adv. 7 (36), eabj1414. doi:10.1126/sciadv.abj1414

PubMed Abstract | CrossRef Full Text | Google Scholar

Choimet, M., Tourrette, A., Marsan, O., Rassu, G., and Drouet, C. (2020). Bio-inspired apatite particles limit skin penetration of drugs for dermatology applications. Acta Biomater. 111, 418–428. doi:10.1016/j.actbio.2020.05.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Correia, D. M., Fernandes, L. C., Fernandes, M. M., Hermenegildo, B., Meira, R. M., Ribeiro, C., et al. (2021). Ionic liquid-based materials for biomedical applications. Nanomater. (Basel, Switz. 11 (9), 2401. doi:10.3390/nano11092401

CrossRef Full Text | Google Scholar

Cumberbatch, M., Dearman, R. J., Griffiths, C. E., and Kimber, I. (2003). Epidermal Langerhans cell migration and sensitisation to chemical allergens. APMIS acta pathologica, Microbiol. Immunol. Scand. 111 (7-8), 797–804. doi:10.1034/j.1600-0463.2003.11107811.x

PubMed Abstract | CrossRef Full Text | Google Scholar

David, D. D. (2014). Prodrug strategies for enhancing the percutaneous absorption of drugs. Mol. (Basel, Switz. 19 (12), 20780–20807. doi:10.3390/molecules191220780

CrossRef Full Text | Google Scholar

Dawber, R. P. (1980). The ultrastructure and growth of human nails. Archives Dermatological Res. 269 (2), 197–204. doi:10.1007/bf00406540

PubMed Abstract | CrossRef Full Text | Google Scholar

Deng, C. C., Hu, Y. F., Zhu, D. H., Cheng, Q., Gu, J. J., Feng, Q. L., et al. (2021). Single-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases. Nat. Commun. 12 (1), 3709. doi:10.1038/s41467-021-24110-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Dhariwala, M. O., and Scharschmidt, T. C. (2021). Baby's skin bacteria: first impressions are long-lasting. Trends Immunol. 42 (12), 1088–1099. doi:10.1016/j.it.2021.10.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Dierking, I., and Al-Zangana, S. (2017). Lyotropic liquid crystal phases from anisotropic nanomaterials. Nanomater. (Basel, Switz. 7 (10), 305. doi:10.3390/nano7100305

CrossRef Full Text | Google Scholar

Do, T. C., Lau, J. W., Sun, C., Liu, S., Kha, K. T., Lim, S. T., et al. (2022). Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras. Sci. Adv. 8 (50), eabq2216. doi:10.1126/sciadv.abq2216

PubMed Abstract | CrossRef Full Text | Google Scholar

Do, T. H., Ma, F., Andrade, P. R., Teles, R., de Andrade Silva, B. J., Hu, C., et al. (2022). TREM2 macrophages induced by human lipids drive inflammation in acne lesions. Sci. Immunol. 7 (73), eabo2787. doi:10.1126/sciimmunol.abo2787

PubMed Abstract | CrossRef Full Text | Google Scholar

Dong, Z., Feng, L., Hao, Y., Chen, M., Gao, M., Chao, Y., et al. (2018). Synthesis of hollow biomineralized CaCO 3 -polydopamine nanoparticles for multimodal imaging-guided cancer photodynamic therapy with reduced skin photosensitivity. J. Am. Chem. Soc. 140 (6), 2165–2178. doi:10.1021/jacs.7b11036

PubMed Abstract | CrossRef Full Text | Google Scholar

Du, H., Yao, C. Y., Peng, H., Jang, B., Li, S. X., Yao, J. L., et al. (2022). Applications of transition metal-doped iron-based nanoparticles in biomedicine. Chin. J. Appl. Chem. 39 (3), 1016. doi:10.19894/j.issn.1000-0518.210394

CrossRef Full Text | Google Scholar

Dudeck, J., Kotrba, J., Immler, R., Hoffmann, A., Voss, M., Alexaki, V. I., et al. (2021). Directional mast cell degranulation of tumor necrosis factor into blood vessels primes neutrophil extravasation. Immunity 54 (3), 468–483.e5. doi:10.1016/j.immuni.2020.12.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Dull, B. J., Salata, K., and Goldman, P. (1987). Role of the intestinal flora in the acetylation of sulfasalazine metabolites. Biochem. Pharmacol. 36 (21), 3772–3774. doi:10.1016/0006-2952(87)90034-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Economidou, S. N., Lamprou, D. A., and Douroumis, D. (2018). 3D printing applications for transdermal drug delivery. Int. J. Pharm. 544 (2), 415–424. doi:10.1016/j.ijpharm.2018.01.031

PubMed Abstract | CrossRef Full Text | Google Scholar

Egorova, K. S., Gordeev, E. G., and Ananikov, V. P. (2017). Biological activity of ionic liquids and their application in pharmaceutics and medicine. Chem. Rev. 117 (10), 7132–7189. doi:10.1021/acs.chemrev.6b00562

PubMed Abstract | CrossRef Full Text | Google Scholar

Elshafie, H. S., and Camele, I. (2017). An overview of the biological effects of some mediterranean essential oils on human health. BioMed Res. Int. 2017, 9268468. doi:10.1155/2017/9268468

PubMed Abstract | CrossRef Full Text | Google Scholar

Enamorado, M., Kulalert, W., Han, S. J., Rao, I., Delaleu, J., Link, V. M., et al. (2023). Immunity to the microbiota promotes sensory neuron regeneration. Cell 186 (3), 607–620.e17. doi:10.1016/j.cell.2022.12.037

PubMed Abstract | CrossRef Full Text | Google Scholar

Eyerich, S., Eyerich, K., Traidl-Hoffmann, C., and Biedermann, T. (2018). Cutaneous barriers and skin immunity: differentiating A connected network. Trends Immunol. 39 (4), 315–327. doi:10.1016/j.it.2018.02.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Falduto, G. H., Pfeiffer, A., Luker, A., Metcalfe, D. D., and Olivera, A. (2021). Emerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications. Pharmacol. Ther. 220, 107718. doi:10.1016/j.pharmthera.2020.107718

PubMed Abstract | CrossRef Full Text | Google Scholar

Feng, J., Luo, J., Yang, P., Du, J., Kim, B. S., and Hu, H. (2018). Piezo2 channel-Merkel cell signaling modulates the conversion of touch to itch. Sci. (New York, N.Y.). 360 (6388), 530–533. doi:10.1126/science.aar5703

PubMed Abstract | CrossRef Full Text | Google Scholar

Fizanne, L., Villard, A., Benabbou, N., Recoquillon, S., Soleti, R., Delage, E., et al. (2023). Faeces-derived extracellular vesicles participate in the onset of barrier dysfunction leading to liver diseases. J. Extracell. vesicles 12 (2), e12303. doi:10.1002/jev2.12303

PubMed Abstract | CrossRef Full Text | Google Scholar

Flori, E., Mastrofrancesco, A., Mosca, S., Ottaviani, M., Briganti, S., Cardinali, G., et al. (2022). Sebocytes contribute to melasma onset. iScience 25 (3), 103871. doi:10.1016/j.isci.2022.103871

PubMed Abstract | CrossRef Full Text | Google Scholar

Fonder, M. A., Mamelak, A. J., Lazarus, G. S., and Chanmugam, A. (2007). Occlusive wound dressings in emergency medicine and acute care. Emerg. Med. Clin. N. Am. 25 (1), 235–242. doi:10.1016/j.emc.2007.01.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Frankel, A. D., and Pabo, C. O. (1988). Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55 (6), 1189–1193. doi:10.1016/0092-8674(88)90263-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Frederiksen, K., Guy, R. H., and Petersson, K. (2015). Formulation considerations in the design of topical, polymeric film-forming systems for sustained drug delivery to the skin. Eur. J. Pharm. Biopharm. 91, 9–15. doi:10.1016/j.ejpb.2015.01.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Fu, Z., Li, S., Han, S., Shi, C., and Zhang, Y. (2022a). Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct. Target. Ther. 7 (1), 93. doi:10.1038/s41392-022-00947-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Gallo, R. L. (2015). S. epidermidis influence on host immunity: more than skin deep. Cell host microbe 17 (2), 143–144. doi:10.1016/j.chom.2015.01.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Gan, B. K., Yong, C. Y., Ho, K. L., Omar, A. R., Alitheen, N. B., and Tan, W. S. (2018). Targeted delivery of cell penetrating peptide virus-like nanoparticles to skin cancer cells. Sci. Rep. 8 (1), 8499. doi:10.1038/s41598-018-26749-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Gao, J., Wang, S., Dong, X., Leanse, L. G., Dai, T., and Wang, Z. (2020). Co-delivery of resolvin D1 and antibiotics with nanovesicles to lungs resolves inflammation and clears bacteria in mice. Commun. Biol. 3 (1), 680. doi:10.1038/s42003-020-01410-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Gao, Y., Zhang, W., Li, L., Wang, Z., Shu, Y., and Wang, J. (2023). Ionic liquid-based gels for biomedical applications. Chem. Eng. J. 452, 139248. doi:10.1016/j.cej.2022.139248

CrossRef Full Text | Google Scholar

Garg, T., Rath, G., and Goyal, A. K. (2015). Comprehensive review on additives of topical dosage forms for drug delivery. Drug Deliv. 22 (8), 969–987. doi:10.3109/10717544.2013.879355

PubMed Abstract | CrossRef Full Text | Google Scholar

Gattu, S., and Maibach, H. I. (2011). Modest but increased penetration through damaged skin: an overview of the in vivo human model. Skin Pharmacol. physiology 24 (1), 2–9. doi:10.1159/000314995

PubMed Abstract | CrossRef Full Text | Google Scholar

Gaydosik, A. M., Tabib, T., Domsic, R., Khanna, D., Lafyatis, R., and Fuschiotti, P. (2021). Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis. Ann. rheumatic Dis. 80 (11), 1453–1460. doi:10.1136/annrheumdis-2021-220209

CrossRef Full Text | Google Scholar

Ge, G., Mandal, K., Haghniaz, R., Li, M., Xiao, X., Carlson, L., et al. (2023). Deep eutectic solvents-based ionogels with ultrafast gelation and high adhesion in harsh environments. Adv. Funct. Mater. 33 (9), 2207388. doi:10.1002/adfm.202207388

PubMed Abstract | CrossRef Full Text | Google Scholar

Ghetti, M., Topouzi, H., Theocharidis, G., Papa, V., Williams, G., Bondioli, E., et al. (2018). Subpopulations of dermal skin fibroblasts secrete distinct extracellular matrix: implications for using skin substitutes in the clinic. Br. J. dermatology 179 (2), 381–393. doi:10.1111/bjd.16255

PubMed Abstract | CrossRef Full Text | Google Scholar

Gilbert, J. A., Krajmalnik-Brown, R., Porazinska, D. L., Weiss, S. J., and Knight, R. (2013). Toward effective probiotics for autism and other neurodevelopmental disorders. Cell 155 (7), 1446–1448. doi:10.1016/j.cell.2013.11.035

PubMed Abstract | CrossRef Full Text | Google Scholar

Glass, D. R., Tsai, A. G., Oliveria, J. P., Hartmann, F. J., Kimmey, S. C., Calderon, A. A., et al. (2020). An integrated multi-omic single-cell atlas of human B cell identity. Immunity 53 (1), 217–232. doi:10.1016/j.immuni.2020.06.013

PubMed Abstract | CrossRef Full Text | Google Scholar

Gomes, A., Aguiar, L., Ferraz, R., Teixeira, C., and Gomes, P. (2021). The emerging role of ionic liquid-based approaches for enhanced skin permeation of bioactive molecules: a snapshot of the past couple of years. Int. J. Mol. Sci. 22 (21), 11991. doi:10.3390/ijms222111991

PubMed Abstract | CrossRef Full Text | Google Scholar

Gong, L., Whirl-Carrillo, M., and Klein, T. E. (2021). PharmGKB, an integrated resource of pharmacogenomic knowledge. Curr. Protoc. 1 (8), e226. doi:10.1002/cpz1.226

PubMed Abstract | CrossRef Full Text | Google Scholar

Grabow, W. W., and Jaeger, L. (2012). siRNA delivery: loaded-up microsponges. Nat. Mater. 11 (4), 268–269. doi:10.1038/nmat3286

PubMed Abstract | CrossRef Full Text | Google Scholar

Green, D. W., Stamboulis, A., and Ben-Nissan, B. (2020). Specifiable biomimetic microsponges for timed release of crystal entrapped biomolecules useful in bone repair. J. Mater. Chem. B 8 (32), 7143–7148. doi:10.1039/d0tb01491e

PubMed Abstract | CrossRef Full Text | Google Scholar

Grzybowski, A. (2008). Cocaine and the eye: a historical overview. Ophthalmol. J. Int. d'ophtalmologie. Int. J. Ophthalmol. Zeitschrift fur Augenheilkunde. 222 (5), 296–301. doi:10.1159/000140625

PubMed Abstract | CrossRef Full Text | Google Scholar

Guidotti, G., Brambilla, L., and Rossi, D. (2017). Cell-penetrating peptides: from basic research to clinics. Trends Pharmacol. Sci. 38 (4), 406–424. doi:10.1016/j.tips.2017.01.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Guillen, S. G., Parres-Gold, J., Ruiz, A., Lucsik, E., Dao, B., Hang, T. K. L., et al. (2022). pH-responsive metal-organic framework thin film for drug delivery. Langmuir ACS J. surfaces colloids 38 (51), 16014–16023. doi:10.1021/acs.langmuir.2c02497

CrossRef Full Text | Google Scholar

Gur, C., Wang, S. Y., Sheban, F., Zada, M., Li, B., Kharouf, F., et al. (2022). LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma. Cell 185 (8), 1373–1388. doi:10.1016/j.cell.2022.03.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Gurbatri, C. R., Lia, I., Vincent, R., Coker, C., Castro, S., Treuting, P. M., et al. (2020). Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies. Sci. Transl. Med. 12 (530), eaax0876. doi:10.1126/scitranslmed.aax0876

PubMed Abstract | CrossRef Full Text | Google Scholar

Gurung, M., Moon, D. C., Choi, C. W., Lee, J. H., Bae, Y. C., Kim, J., et al. (2011). Staphylococcus aureus produces membrane-derived vesicles that induce host cell death. PloS one 6 (11), e27958. doi:10.1371/journal.pone.0027958

PubMed Abstract | CrossRef Full Text | Google Scholar

Hallal, S., Tűzesi, Á., Grau, G. E., Buckland, M. E., and Alexander, K. L. (2022). Understanding the extracellular vesicle surface for clinical molecular biology. J. Extracell. vesicles 11 (10), e12260. doi:10.1002/jev2.12260

PubMed Abstract | CrossRef Full Text | Google Scholar

Hao, J., Ghosh, P., Li, S. K., Newman, B., Kasting, G. B., and Raney, S. G. (2016). Heat effects on drug delivery across human skin. Expert Opin. drug Deliv. 13 (5), 755–768. doi:10.1517/17425247.2016.1136286

PubMed Abstract | CrossRef Full Text | Google Scholar

Haque, T., and Talukder, M. M. U. (2018). Chemical enhancer: a simplistic way to modulate barrier function of the stratum corneum. Adv. Pharm. Bull. 8 (2), 169–179. doi:10.15171/apb.2018.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Haraguchi, K., Uyama, K., and Tanimoto, H. (2011). Self-healing in nanocomposite hydrogels. Macromol. rapid Commun. 32 (16), 1253–1258. doi:10.1002/marc.201100248

PubMed Abstract | CrossRef Full Text | Google Scholar

Harding, C., Heuser, J., and Stahl, P. (1984). Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur. J. Cell Biol. 35 (2), 256–263.

PubMed Abstract | Google Scholar

Hasegawa, T., Oka, T., Son, H. G., Oliver-García, V. S., Azin, M., Eisenhaure, T. M., et al. (2023). Cytotoxic CD4 + T cells eliminate senescent cells by targeting cytomegalovirus antigen. Cell 186 (7), 1417–1431. doi:10.1016/j.cell.2023.02.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Hemmati, A. A., Aghel, N., Rashidi, I., and Gholampur-Aghdami, A. (2011). Topical grape (Vitis vinifera) seed extract promotes repair of full thickness wound in rabbit. Int. wound J. 8 (5), 514–520. doi:10.1111/j.1742-481x.2011.00833.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Herold, H. M., Döbl, A., Wohlrab, S., Humenik, M., and Scheibel, T. (2020). Designed spider silk-based drug carrier for redox- or pH-triggered drug release. Biomacromolecules 21 (12), 4904–4912. doi:10.1021/acs.biomac.0c01138

PubMed Abstract | CrossRef Full Text | Google Scholar

Hissae Yassue-Cordeiro, P., Zandonai, C. H., Pereira Genesi, B., Santos Lopes, P., Sanchez-Lopez, E., Garcia, M. L., et al. (2019). Development of chitosan/silver sulfadiazine/zeolite composite films for wound dressing. Dress. Pharm. 11 (10), 535. doi:10.3390/pharmaceutics11100535

CrossRef Full Text | Google Scholar

Hjelm, A., Söderström, B., Vikström, D., Jong, W. S., Luirink, J., and de Gier, J. W. (2015). Autotransporter-based antigen display in bacterial ghosts. Appl. Environ. Microbiol. 81 (2), 726–735. doi:10.1128/aem.02733-14

PubMed Abstract | CrossRef Full Text | Google Scholar

Huang, K., Wang, J., Zhang, Q., Yuan, K., Yang, Y., Li, F., et al. (2022). Sub 150 nm nanoscale gallium based metal–organic frameworks armored antibiotics as super penetrating bombs for eradicating persistent bacteria. Adv. Funct. Mater. 32 (43), 2204906. doi:10.1002/adfm.202204906

CrossRef Full Text | Google Scholar

Huang, W., Zhang, Q., Li, W., Yuan, M., Zhou, J., Hua, L., et al. (2020). Development of novel nanoantibiotics using an outer membrane vesicle-based drug efflux mechanism. J. Control. release official J. Control. Release Soc. 317, 1–22. doi:10.1016/j.jconrel.2019.11.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Huang, Y. S., Tseng, W. Y., Clanchy, F. I. L., Topping, L. M., Ogbechi, J., McNamee, K., et al. (2021). Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis. Proc. Natl. Acad. Sci. U. S. A. 118 (19), e2100939118. doi:10.1073/pnas.2100939118

PubMed Abstract | CrossRef Full Text | Google Scholar

Hughes, T. K., Wadsworth, M. H. 2nd., Gierahn, T. M., Do, T., Weiss, D., Andrade, P. R., et al. (2020). Second-strand synthesis-based massively parallel scRNA-seq reveals cellular states and molecular features of human inflammatory skin pathologies. Immunity 53 (4), 878–894. doi:10.1016/j.immuni.2020.09.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Humeau, M., Boniface, K., and Bodet, C. (2022). Cytokine-mediated crosstalk between keratinocytes and T cells in atopic dermatitis. Front. Immunol. 13, 801579. doi:10.3389/fimmu.2022.801579

PubMed Abstract | CrossRef Full Text | Google Scholar

Idson, B. (1975). Percutaneous absorption. J. Pharm. Sci. 64, 901–924. doi:10.1002/jps.2600640604

PubMed Abstract | CrossRef Full Text | Google Scholar

Ishii, H., Todo, H., and Sugibayashi, K. (2010). Effect of thermodynamic activity on skin permeation and skin concentration of triamcinolone acetonide. Chem. Pharm. Bull. 58 (4), 556–561. doi:10.1248/cpb.58.556

PubMed Abstract | CrossRef Full Text | Google Scholar

Ji, S., Zhu, Z., Sun, X., and Fu, X. (2021). Functional hair follicle regeneration: an updated review. Signal Transduct. Target. Ther. 6 (1), 66. doi:10.1038/s41392-020-00441-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Jimbow, K., Fitzpatrick, T. B., and Quevedo, W. C. (1986). Formation, chemical composition and function of melanin pigments. Biol. Integument, 278–292. doi:10.1007/978-3-662-00989-5_16

CrossRef Full Text | Google Scholar

Jindal, S., Awasthi, R., Goyal, K., and Kulkarni, G. T. (2022). Hydrogels for localized drug delivery: a special emphasis on dermatologic applications. Dermatol. Ther. 35 (11), e15830. doi:10.1111/dth.15830

PubMed Abstract | CrossRef Full Text | Google Scholar

Jing, Q., Ruan, H., Li, J., Wang, Z., Pei, L., Hu, H., et al. (2021). Keratinocyte membrane-mediated nanodelivery system with dissolving microneedles for targeted therapy of skin diseases. Biomaterials 278, 121142. doi:10.1016/j.biomaterials.2021.121142

PubMed Abstract | CrossRef Full Text | Google Scholar

Jun, S. H., Lee, J. H., Kim, S. I., Choi, C. W., Park, T. I., Jung, H. R., et al. (2017). Staphylococcus aureus-derived membrane vesicles exacerbate skin inflammation in atopic dermatitis. Clin. Exp. allergy J. Br. Soc. Allergy Clin. Immunol. 47 (1), 85–96. doi:10.1111/cea.12851

PubMed Abstract | CrossRef Full Text | Google Scholar

Junqueira, M. V., and Bruschi, M. L. (2018). A review about the drug delivery from microsponges. AAPS PharmSciTech 19 (4), 1501–1511. doi:10.1208/s12249-018-0976-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Kabashima, K., Honda, T., Ginhoux, F., and Egawa, G. (2019). The immunological anatomy of the skin. Nat. Rev. Immunol. 19 (1), 19–30. doi:10.1038/s41577-018-0084-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Karnell, J. L., Wu, Y., Mittereder, N., Smith, M. A., Gunsior, M., Yan, L., et al. (2021). Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus. Sci. Transl. Med. 13 (595), eabf8442. doi:10.1126/scitranslmed.abf8442

PubMed Abstract | CrossRef Full Text | Google Scholar

Katila, N., Duwa, R., Bhurtel, S., Khanal, S., Maharjan, S., Jeong, J. H., et al. (2022). Enhancement of blood-brain barrier penetration and the neuroprotective effect of resveratrol. J. Control. release official J. Control. Release Soc. 346, 1–19. doi:10.1016/j.jconrel.2022.04.003

CrossRef Full Text | Google Scholar

Kim, M., Kim, S. M., Kwon, S., Park, T. J., and Kang, H. Y. (2019a). Senescent fibroblasts in melasma pathophysiology. Exp. Dermatol. 28 (6), 719–722. doi:10.1111/exd.13814

PubMed Abstract | CrossRef Full Text | Google Scholar

Kobayashi, T., Ricardo-Gonzalez, R. R., and Moro, K. (2020). Skin-Resident innate lymphoid cells - cutaneous innate guardians and regulators. Trends Immunol. 41 (2), 100–112. doi:10.1016/j.it.2019.12.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Koh, A., Mannerås-Holm, L., Yunn, N. O., Nilsson, P. M., Ryu, S. H., Molinaro, A., et al. (2020). Microbial imidazole propionate affects responses to metformin through p38γ-dependent inhibitory AMPK phosphorylation. Cell Metab. 32 (4), 643–653. doi:10.1016/j.cmet.2020.07.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Kratofil, R. M., Shim, H. B., Shim, R., Lee, W. Y., Labit, E., Sinha, S., et al. (2022). A monocyte-leptin-angiogenesis pathway critical for repair post-infection. Nature 609 (7925), 166–173. doi:10.1038/s41586-022-05044-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Kudela, P., Koller, V. J., and Lubitz, W. (2010). Bacterial ghosts (BGs)--advanced antigen and drug delivery system. Vaccine 28 (36), 5760–5767. doi:10.1016/j.vaccine.2010.06.087

PubMed Abstract | CrossRef Full Text | Google Scholar

Kumar, S., and Nanda, A. (2018). Approaches to design of pharmaceutical cocrystals: a review. Mol. Cryst. Liq. Cryst. 667, 54–77. doi:10.1080/15421406.2019.1577462

CrossRef Full Text | Google Scholar

Kunde, S. S., and Wairkar, S. (2021). Platelet membrane camouflaged nanoparticles: biomimetic architecture for targeted therapy. Int. J. Pharm. 598, 120395. doi:10.1016/j.ijpharm.2021.120395

PubMed Abstract | CrossRef Full Text | Google Scholar

Lahav-Mankovski, N., Prasad, P. K., Oppenheimer-Low, N., Raviv, G., Dadosh, T., Unger, T., et al. (2020). Decorating bacteria with self-assembled synthetic receptors. Nat. Commun. 11 (1), 1299. doi:10.1038/s41467-020-14336-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, Y. W., Kim, J. K., Bozuyuk, U., Dogan, N. O., Khan, M. T. A., Shiva, A., et al. (2023). Multifunctional 3D-printed pollen grain-inspired hydrogel microrobots for on-demand anchoring and cargo delivery. Adv. Mater. Deerf. Beach, Fla.) 35 (10), e2209812. doi:10.1002/adma.202209812

CrossRef Full Text | Google Scholar

Lei, Z., Chen, B., Koo, Y. M., and MacFarlane, D. R. (2017). Introduction: ionic liquids. Chem. Rev. 117 (10), 6633–6635. doi:10.1021/acs.chemrev.7b00246

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, J., Ding, Y., Cheng, Q., Gao, C., Wei, J., Wang, Z., et al. (2022a). Supramolecular erythrocytes-hitchhiking drug delivery system for specific therapy of acute pneumonia. J. Control. release official J. Control. Release Soc. 350, 777–786. doi:10.1016/j.jconrel.2022.08.029

CrossRef Full Text | Google Scholar

Li, J., Lin, S., Vanhoutte, P. M., Woo, C. W., and Xu, A. (2016). Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in apoe-/- mice. Circulation 133 (24), 2434–2446. doi:10.1161/circulationaha.115.019645

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, S., Dong, S., Xu, W., Tu, S., Yan, L., Zhao, C., et al. (2018). Antibacterial hydrogels. Adv. Sci. (Weinheim, Baden-Wurttemberg, Ger. 5 (5), 1700527. doi:10.1002/advs.201700527

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, T., Wang, Y., Li, S., Liu, X., and Sun, J. (2020). Mechanically robust, elastic, and healable ionogels for highly sensitive ultra-durable ionic skins. Adv. Mater. Deerf. Beach, Fla.) 32 (32), e2002706. doi:10.1002/adma.202002706

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Feng, S., Dai, P., Liu, F., Shang, Y., Yang, Q., et al. (2022b). Tailored Trojan horse nanocarriers for enhanced redox-responsive drug delivery. J. Control. release official J. Control. Release Soc. 342, 201–209. doi:10.1016/j.jconrel.2022.01.006

CrossRef Full Text | Google Scholar

Li, Y., Hu, D., Pan, M., Qu, Y., Chu, B., Liao, J., et al. (2022d). Near-infrared light and redox dual-activatable nanosystems for synergistically cascaded cancer phototherapy with reduced skin photosensitization. Biomaterials 288, 121700. doi:10.1016/j.biomaterials.2022.121700

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Ma, X., Yue, Y., Zhang, K., Cheng, K., Feng, Q., et al. (2022c). Rapid surface display of mRNA antigens by bacteria-derived outer membrane vesicles for a personalized tumor vaccine. Adv. Mater. Deerf. Beach, Fla.) 34 (20), e2109984. doi:10.1002/adma.202109984

CrossRef Full Text | Google Scholar

Li, Z., Wang, Y., Liu, J., Rawding, P., Bu, J., Hong, S., et al. (2021). Chemically and biologically engineered bacteria-based delivery systems for emerging diagnosis and advanced therapy. Adv. Mater. 33 (38), 2102580. doi:10.1002/adma.202102580

CrossRef Full Text | Google Scholar

Li, Z., Wang, Y., Liu, J., Rawding, P., Bu, J., Hong, S., et al. (2021). Chemically and biologically engineered bacteria-based delivery systems for emerging diagnosis and advanced therapy. Adv. Mater. Deerf. Beach, Fla.) 33 (38), e2102580. doi:10.1002/adma.202102580

CrossRef Full Text | Google Scholar

Li, Z., Zhu, Y., and Matson, J. B. (2022e). pH-responsive self-assembling peptide-based biomaterials: designs and applications. ACS Appl. bio Mater. 5 (10), 4635–4651. Online ahead of print. doi:10.1021/acsabm.2c00188

CrossRef Full Text | Google Scholar

Lien, E., and Tong, G. (1973). Physicochemical properties and percutaneous absorption of drugs. J. Soc. Cosmet. Chem. 24, 371–384.

Google Scholar

Lima, W. G., Brito, J. C. M., and da Cruz Nizer, W. S. (2021). Bee products as a source of promising therapeutic and chemoprophylaxis strategies against COVID-19 (SARS-CoV-2). Phytotherapy Res. PTR 35 (2), 743–750. doi:10.1002/ptr.6872

CrossRef Full Text | Google Scholar

Liu, H., Jiang, W., Yang, Z., Chen, X., Yu, D. G., and Shao, J. (2022b). Hybrid films prepared from a combination of electrospinning and casting for offering a dual-phase drug release. Polymers 14 (11), 2132. doi:10.3390/polym14112132

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, H., Zhang, H., Han, Y., Hu, Y., Geng, Z., and Su, J. (2022a). Bacterial extracellular vesicles-based therapeutic strategies for bone and soft tissue tumors therapy. Theranostics 12 (15), 6576–6594. doi:10.7150/thno.78034

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, H., Zhang, H., Wang, S., Cui, J., Weng, W., Liu, X., et al. (2023c). Bone-targeted bioengineered bacterial extracellular vesicles delivering siRNA to ameliorate osteoporosis. Compos. Part B Eng. 255, 110610. doi:10.1016/j.compositesb.2023.110610

CrossRef Full Text | Google Scholar

Liu, J., Yuan, Y., Cheng, Y., Fu, D., Chen, Z., Wang, Y., et al. (2022c). Copper-based metal-organic framework overcomes cancer chemoresistance through systemically disrupting dynamically balanced cellular redox homeostasis. J. Am. Chem. Soc. 144 (11), 4799–4809. doi:10.1021/jacs.1c11856

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, Q., Zaba, L. C., Satpathy, A. T., Longmire, M., Zhang, W., Li, K., et al. (2020). Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis. Nat. Commun. 11 (1), 5843. doi:10.1038/s41467-020-19702-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, X., Qin, Y., Dong, L., Han, Z., Liu, T., Tang, Y., et al. (2023a). Living symbiotic bacteria-involved skin dressing to combat indigenous pathogens for microbiome-based biotherapy toward atopic dermatitis. Bioact. Mater. 21, 253–266. doi:10.1016/j.bioactmat.2022.08.019

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, X., Zhu, R., Luo, Y., Wang, S., Zhao, Y., Qiu, Z., et al. (2021). Distinct human Langerhans cell subsets orchestrate reciprocal functions and require different developmental regulation. Immunity 54 (10), 2305–2320. doi:10.1016/j.immuni.2021.08.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, X. Z., Wen, Z. J., Li, Y. M., Sun, W. R., Hu, X. Q., Zhu, J. Z., et al. (2023d). Bioengineered bacterial membrane vesicles with multifunctional nanoparticles as a versatile platform for cancer immunotherapy. ACS Appl. Mater. interfaces 15 (3), 3744–3759. doi:10.1021/acsami.2c18244

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, Y., Zhang, M., Wang, X., Yang, F., Cao, Z., Wang, L., et al. (2023b). Dressing bacteria with a hybrid immunoactive nanosurface to elicit dual anticancer and antiviral immunity. Adv. Mater. Deerf. Beach, Fla. 35 (11). doi:10.1002/adma.202210949

CrossRef Full Text | Google Scholar

Liu, Z., Hu, X., Liang, Y., Yu, J., Li, H., Shokhirev, M. N., et al. (2022d). Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche. Nat. Immunol. 23 (7), 1086–1097. doi:10.1038/s41590-022-01244-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Lloren, K. K. S., Jawalagatti, V., Hewawaduge, C., Chandran, S., Park, J. Y., and Lee, J. H. (2023). Salmonella-mediated oral delivery of multiple-target vaccine constructs with conserved and variable regions of SARS-CoV-2 protect against the Delta and Omicron variants in hamster. Microbes Infect. 25 (5), 105101. doi:10.1016/j.micinf.2023.105101

PubMed Abstract | CrossRef Full Text | Google Scholar

López-Sanz, C., Jimenéz-Saiz, R., and Ehlers, A. M. (2021). Local inflammation enables a basophil-neuronal circuITCH in atopic dermatitis. Allergy 77 (2), 708–710. doi:10.1111/all.15026

PubMed Abstract | CrossRef Full Text | Google Scholar

Lotfy, N. M., Ahmed, M. A., El Hoffy, N. M., Bendas, E. R., and Morsi, N. M. (2022). Development and optimization of amphiphilic self-assembly into nanostructured liquid crystals for transdermal delivery of an antidiabetic SGLT2 inhibitor. Drug Deliv. 29 (1), 3340–3357. doi:10.1080/10717544.2022.2144546

PubMed Abstract | CrossRef Full Text | Google Scholar

Lu, H., Xu, S., Guo, Z., Zhao, M., and Liu, Z. (2021). Redox-responsive molecularly imprinted nanoparticles for targeted intracellular delivery of protein toward cancer therapy. ACS Nano 15 (11), 18214–18225. doi:10.1021/acsnano.1c07166

PubMed Abstract | CrossRef Full Text | Google Scholar

Luessi, F., Zipp, F., and Witsch, E. (2016). Dendritic cells as therapeutic targets in neuroinflammation. Cell. Mol. life Sci. CMLS 73 (13), 2425–2450. doi:10.1007/s00018-016-2170-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Lum, F. M., Torres-Ruesta, A., Tay, M. Z., Lin, R. T. P., Lye, D. C., Rénia, L., et al. (2022). Monkeypox: disease epidemiology, host immunity and clinical interventions. Nat. Rev. Immunol. 22 (10), 597–613. doi:10.1038/s41577-022-00775-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, T., Nash, G. T., Xu, Z., Jiang, X., Liu, J., and Lin, W. (2021). Nanoscale metal-organic framework confines zinc-phthalocyanine photosensitizers for enhanced photodynamic therapy. J. Am. Chem. Soc. 143 (34), 13519–13524. doi:10.1021/jacs.1c07379

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, Z., Li, W., Yan, J., and Sun, J. (2022). Roles of ionic liquids in adjusting nature of ionogels: a mini review. Adv. Funct. Mater. 32 (32), 2203988. doi:10.1002/adfm.202203988

CrossRef Full Text | Google Scholar

Luo, Z., Lu, Y., Shi, Y., Jiang, M., Shan, X., Li, X., et al. (2023). Neutrophil hitchhiking for drug delivery to the bone marrow. Nat. Nanotechnol. 18 (6), 647–656. doi:10.1038/s41565-023-01374-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, L., Chen, C., Liu, D., Huang, Z., Li, J., Liu, H., et al. (2023). Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair. Bioact. Mater. 19, 626–641. doi:10.1016/j.bioactmat.2022.04.022

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, Q., Fan, Q., Han, X., Dong, Z., Xu, J., Bai, J., et al. (2021b). Platelet-derived extracellular vesicles to target plaque inflammation for effective anti-atherosclerotic therapy. J. Control. release official J. Control. Release Soc. 329, 445–453. doi:10.1016/j.jconrel.2020.11.064

CrossRef Full Text | Google Scholar

Ma, Y., Cui, L., Wang, M., Sun, Q., Liu, K., and Wang, J. (2021a). A novel and efficient high-yield method for preparing bacterial ghosts. Toxins 13 (6), 420. doi:10.3390/toxins13060420

PubMed Abstract | CrossRef Full Text | Google Scholar

Macht, D. I. (1938). The absorption of drugs and poisons through the skin and mucous membranes. J. Am. Med. Assoc. 110 (6), 409–414. doi:10.1001/JAMA.1938.02790060001001

CrossRef Full Text | Google Scholar

Macri, C., Pang, E. S., Patton, T., and O'Keeffe, M. (2018). Dendritic cell subsets. Seminars Cell and Dev. Biol. 84, 11–21. doi:10.1016/j.semcdb.2017.12.009

CrossRef Full Text | Google Scholar

Magnusson, B. M., Anissimov, Y. G., Cross, S. E., and Roberts, M. S. (2004). Molecular size as the main determinant of solute maximum flux across the skin. J. Investigative Dermatology 122 (4), 993–999. doi:10.1111/j.0022-202X.2004.22413.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Mahant, S., Kumar, S., Nanda, S., and Rao, R. (2020). Microsponges for dermatological applications: perspectives and challenges. Asian J. Pharm. Sci. 15 (3), 273–291. doi:10.1016/j.ajps.2019.05.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Marwah, H., Garg, T., Goyal, A. K., and Rath, G. (2016). Permeation enhancer strategies in transdermal drug delivery. Drug Deliv. 23 (2), 564–578. doi:10.3109/10717544.2014.935532

PubMed Abstract | CrossRef Full Text | Google Scholar

Mazid, R. R., Divisekera, U., Yang, W., Ranganathan, V., MacFarlane, D. R., Cortez-Jugo, C., et al. (2014). Biological stability and activity of siRNA in ionic liquids. Chem. Commun. Camb. Engl. 50 (88), 13457–13460. doi:10.1039/c4cc05086j

PubMed Abstract | CrossRef Full Text | Google Scholar

McDonald, S., Murphy, T., Imberti, S., Warr, G. G., and Atkin, R. (2018). Amphiphilically nanostructured deep eutectic solvents. J. Phys. Chem. Lett. 9 (14), 3922–3927. doi:10.1021/acs.jpclett.8b01720

PubMed Abstract | CrossRef Full Text | Google Scholar

Md Moshikur, R., Shimul, I. M., Uddin, S., Wakabayashi, R., Moniruzzaman, M., and Goto, M. (2022). Transformation of hydrophilic drug into oil-miscible ionic liquids for transdermal drug delivery. ACS Appl. Mater. interfaces 14 (50), 55332–55341. doi:10.1021/acsami.2c15636

PubMed Abstract | CrossRef Full Text | Google Scholar

Mehta, R. S., Mayers, J. R., Zhang, Y., Bhosle, A., Glasser, N. R., Nguyen, L. H., et al. (2023). Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease. Nat. Med. 29 (3), 700–709. doi:10.1038/s41591-023-02217-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Menegatti, S., Zakrewsky, M., Kumar, S., De Oliveira, J. S., Muraski, J. A., and Mitragotri, S. (2016). De novo design of skin-penetrating peptides for enhanced transdermal delivery of peptide drugs. Adv. Healthc. Mater. 5 (5), 602–609. doi:10.1002/adhm.201500634

PubMed Abstract | CrossRef Full Text | Google Scholar

Metwaly, A. M., Ghoneim, M. M., Eissa, I. H., Elsehemy, I. A., Mostafa, A. E., Hegazy, M. M., et al. (2021). Traditional ancient Egyptian medicine: a review. Saudi J. Biol. Sci. 28 (10), 5823–5832. doi:10.1016/j.sjbs.2021.06.044

PubMed Abstract | CrossRef Full Text | Google Scholar

Michaels, A. S., Chandrasekaran, S. K., and Shaw, J. E. (1975). Drug permeation through human skin: theory and in vitro experimental measurement. AIChE J. 21 (5), 985–996. doi:10.1002/aic.690210522

CrossRef Full Text | Google Scholar

Michalek, J., Hezova, R., Turanek-Knötigova, P., Gabkova, J., Strioga, M., Lubitz, W., et al. (2017). Oncolysate-loaded Escherichia coli bacterial ghosts enhance the stimulatory capacity of human dendritic cells. CII 66 (2), 149–159. doi:10.1007/s00262-016-1932-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Milletti, F. (2012). Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov. today 17 (15-16), 850–860. doi:10.1016/j.drudis.2012.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Mitov, M. (2017). Cholesteric liquid crystals in living matter. Soft matter 13 (23), 4176–4209. doi:10.1039/c7sm00384f

PubMed Abstract | CrossRef Full Text | Google Scholar

Mohammed, Y., Holmes, A., Kwok, P. C. L., Kumeria, T., Namjoshi, S., Imran, M., et al. (2022). Advances and future perspectives in epithelial drug delivery. Adv. drug Deliv. Rev. 186, 114293. doi:10.1016/j.addr.2022.114293

PubMed Abstract | CrossRef Full Text | Google Scholar

Mojumdar, E. H., Pham, Q. D., Topgaard, D., and Sparr, E. (2017). Skin hydration: interplay between molecular dynamics, structure and water uptake in the stratum corneum. Sci. Rep. 7 (1), 15712. doi:10.1038/s41598-017-15921-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Monti, D., Egiziano, E., Burgalassi, S., Chetoni, P., Chiappe, C., Sanzone, A., et al. (2017). Ionic liquids as potential enhancers for transdermal drug delivery. Int. J. Pharm. 516 (1-2), 45–51. doi:10.1016/j.ijpharm.2016.11.020

PubMed Abstract | CrossRef Full Text | Google Scholar

Moor, M., Banerjee, O., Abad, Z. S. H., Krumholz, H. M., Leskovec, J., Topol, E. J., et al. (2023). Foundation models for generalist medical artificial intelligence. Nature 616 (7956), 259–265. doi:10.1038/s41586-023-05881-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Mora-Raimundo, P., Lozano, D., Benito, M., Mulero, F., Manzano, M., and Vallet-Regí, M. (2021). Osteoporosis remission and new bone formation with mesoporous silica nanoparticles. Adv. Sci. (Weinheim, Baden-Wurttemberg, Ger. 8 (16), e2101107. doi:10.1002/advs.202101107

CrossRef Full Text | Google Scholar

Ñahui Palomino, R. A., Vanpouille, C., Costantini, P. E., and Margolis, L. (2021). Microbiota-host communications: bacterial extracellular vesicles as a common language. PLoS Pathog. 17 (5), e1009508. doi:10.1371/journal.ppat.1009508

PubMed Abstract | CrossRef Full Text | Google Scholar

Ñahui Palomino, R. A., Vanpouille, C., Laghi, L., Parolin, C., Melikov, K., Backlund, P., et al. (2019). Extracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues. Nat. Commun. 10 (1), 5656. doi:10.1038/s41467-019-13468-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Nakatsuji, T., Chen, T. H., Butcher, A. M., Trzoss, L. L., Nam, S. J., Shirakawa, K. T., et al. (2018). A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci. Adv. 4 (2), eaao4502. doi:10.1126/sciadv.aao4502

PubMed Abstract | CrossRef Full Text | Google Scholar

Narain, A., Asawa, S., Chhabria, V., and Patil-Sen, Y. (2017). Cell membrane coated nanoparticles: next-generation therapeutics. Nanomedicine Lond. Engl. 12 (21), 2677–2692. doi:10.2217/nnm-2017-0225

PubMed Abstract | CrossRef Full Text | Google Scholar

Narayanaswamy, R., and Torchilin, V. P. (2019). Hydrogels and their applications in targeted drug delivery. Mol. (Basel, Switz. 24 (3), 603. doi:10.3390/molecules24030603

PubMed Abstract | CrossRef Full Text | Google Scholar

Nie, W., Yu, T., Liu, X., Wang, B., Li, T., Wu, Y., et al. (2021). Non-viral vector mediated CKb11 with folic acid modification regulates macrophage polarization and DC maturation to elicit immune response against cancer. Bioact. Mater. 6 (11), 3678–3691. doi:10.1016/j.bioactmat.2021.03.031

PubMed Abstract | CrossRef Full Text | Google Scholar

Nishikawa, M., Ogawa, K., Umeki, Y., Mohri, K., Kawasaki, Y., Watanabe, H., et al. (2014). Injectable, self-gelling, biodegradable, and immunomodulatory DNA hydrogel for antigen delivery. J. Control. release official J. Control. Release Soc. 180, 25–32. doi:10.1016/j.jconrel.2014.02.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Niu, Y. Q., Liu, J. H., Aymonier, C., Fermani, S., Kralj, D., Falini, G., et al. (2022). Calcium carbonate: controlled synthesis, surface functionalization, and nanostructured materials. Chem. Soc. Rev. 51 (18), 7883–7943. doi:10.1039/d1cs00519g

PubMed Abstract | CrossRef Full Text | Google Scholar

Ogawa, R. (2017). Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis. Int. J. Mol. Sci. 18 (3), 606. doi:10.3390/ijms18030606

PubMed Abstract | CrossRef Full Text | Google Scholar

Oh, S. J., Lee, E. N., Park, J. H., Lee, J. K., Cho, G. J., Park, I. H., et al. (2022). Anti-viral activities of umbilical cord mesenchymal stem cell-derived small extracellular vesicles against human respiratory viruses. Front. Cell. Infect. Microbiol. 12, 850744. doi:10.3389/fcimb.2022.850744

PubMed Abstract | CrossRef Full Text | Google Scholar

Oliveira, G., Stromhaug, K., Cieri, N., Iorgulescu, J. B., Klaeger, S., Wolff, J. O., et al. (2022). Landscape of helper and regulatory antitumour CD4 + T cells in melanoma. Nature 605 (7910), 532–538. doi:10.1038/s41586-022-04682-5

PubMed Abstract | CrossRef Full Text | Google Scholar

O'Neill, A. M., Liggins, M. C., Seidman, J. S., Do, T. H., Li, F., Cavagnero, K. J., et al. (2022). Antimicrobial production by perifollicular dermal preadipocytes is essential to the pathophysiology of acne. Sci. Transl. Med. 14 (632), eabh1478. doi:10.1126/scitranslmed.abh1478

PubMed Abstract | CrossRef Full Text | Google Scholar

Padula, C., Nicoli, S., Pescina, S., and Santi, P. (2019). Thin polymeric films for the topical delivery of propranolol. Colloids surfaces. B, Biointerfaces. 174, 582–586. doi:10.1016/j.colsurfb.2018.11.022

PubMed Abstract | CrossRef Full Text | Google Scholar

Pan, W. L., Tan, Y., Meng, W., Huang, N. H., Zhao, Y. B., Yu, Z. Q., et al. (2022). Microenvironment-driven sequential ferroptosis, photodynamic therapy, and chemotherapy for targeted breast cancer therapy by a cancer-cell-membrane-coated nanoscale metal-organic framework. Biomaterials 283, 121449. doi:10.1016/j.biomaterials.2022.121449

PubMed Abstract | CrossRef Full Text | Google Scholar

Pastore, M. N., Kalia, Y. N., Horstmann, M., and Roberts, M. S. (2015). Transdermal patches: history, development and pharmacology. Br. J. Pharmacol. 172 (9), 2179–2209. doi:10.1111/bph.13059

PubMed Abstract | CrossRef Full Text | Google Scholar

Patel, D. K., Jung, E., Priya, S., Won, S. Y., and Han, S. S. (2024). Recent advances in biopolymer-based hydrogels and their potential biomedical applications. Carbohydr. Polym. 323, 121408. doi:10.1016/j.carbpol.2023.121408

PubMed Abstract | CrossRef Full Text | Google Scholar

Pei, P., Zhang, Y., Jiang, Y., Shen, W., Chen, H., Yang, S., et al. (2022). Pleiotropic immunomodulatory functions of radioactive inactivated bacterial vectors for enhanced cancer radio-immunotherapy. ACS Nano 16 (7), 11325–11337. doi:10.1021/acsnano.2c04982

PubMed Abstract | CrossRef Full Text | Google Scholar

Peralta, M. F., Guzmán, M. L., Pérez, A. P., Apezteguia, G. A., Fórmica, M. L., Romero, E. L., et al. (2018). Liposomes can both enhance or reduce drugs penetration through the skin. Sci. Rep. 8 (1), 13253. doi:10.1038/s41598-018-31693-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Peskoller, M., Bhosale, A., Göbel, K., Löhr, J., Miceli, S., Perot, S., et al. (2022). How to build and regenerate a functional skin barrier: the adhesive and cell shaping travels of a keratinocyte. J. investigative dermatology 142 (4), 1020–1025. doi:10.1016/j.jid.2021.12.034

CrossRef Full Text | Google Scholar

Pieri, L., Domenici, L., and Romagnoli, P. (2001). Langerhans cells differentiation: a three-act play. Italian J. Anat. embryology = Archivio italiano di anatomia ed embriologia 106 (1), 47–69.

PubMed Abstract | Google Scholar

Poon, M. M. L., Caron, D. P., Wang, Z., Wells, S. B., Chen, D., Meng, W., et al. (2023). Tissue adaptation and clonal segregation of human memory T cells in barrier sites. Nat. Immunol. 24 (2), 309–319. doi:10.1038/s41590-022-01395-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Potten, C. S., and Allen, T. D. (1976). A model implicating the Langerhans cell in keratinocyte proliferation control. Differ. Res. Biol. Divers. 5 (1), 43–47. doi:10.1111/j.1432-0436.1976.tb00890.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Proksch, E., Brandner, J. M., and Jensen, J. M. (2008). The skin: an indispensable barrier. Exp. Dermatol. 17 (12), 1063–1072. doi:10.1111/j.1600-0625.2008.00786.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Qian, R. C., Zhou, Z. R., Guo, W., Wu, Y., Yang, Z., and Lu, Y. (2021). Cell surface engineering using DNAzymes: metal ion mediated control of cell-cell interactions. J. Am. Chem. Soc. 143 (15), 5737–5744. doi:10.1021/jacs.1c00060

PubMed Abstract | CrossRef Full Text | Google Scholar

Qian, W., Texter, J., and Yan, F. (2017). Frontiers in poly(ionic liquid)s: syntheses and applications. Chem. Soc. Rev. 46 (4), 1124–1159. doi:10.1039/c6cs00620e

PubMed Abstract | CrossRef Full Text | Google Scholar

Qiao, S., Liu, C., Sun, L., Wang, T., Dai, H., Wang, K., et al. (2022). Gut Parabacteroides merdae protects against cardiovascular damage by enhancing branched-chain amino acid catabolism. Nat. Metab. 4 (10), 1271–1286. doi:10.1038/s42255-022-00649-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Qiu, Z., Zhu, Z., Liu, X., Chen, B., Yin, H., Gu, C., et al. (2022). A dysregulated sebum-microbial metabolite-IL-33 axis initiates skin inflammation in atopic dermatitis. J. Exp. Med. 219 (10), e20212397. doi:10.1084/jem.20212397

PubMed Abstract | CrossRef Full Text | Google Scholar

Rahman, M., Almalki, W. H., Panda, S. K., Das, A. K., Alghamdi, S., Soni, K., et al. (2022). Therapeutic application of microsponges-based drug delivery systems. Curr. Pharm. Des. 28 (8), 595–608. doi:10.2174/1381612828666220118121536

PubMed Abstract | CrossRef Full Text | Google Scholar

Raman, V., Van Dessel, N., Hall, C. L., Wetherby, V. E., Whitney, S. A., Kolewe, E. L., et al. (2021). Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases. Nat. Commun. 12 (1), 6116. doi:10.1038/s41467-021-26367-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Ramanunny, A. K., Wadhwa, S., Gulati, M., Singh, S. K., Kapoor, B., Dureja, H., et al. (2021). Nanocarriers for treatment of dermatological diseases: principle, perspective and practices. Eur. J. Pharmacol. 890, 173691. doi:10.1016/j.ejphar.2020.173691

PubMed Abstract | CrossRef Full Text | Google Scholar

Ramezani-Dakhel, H., Sadati, M., Zhang, R., Rahimi, M., Kurtenbach, K., Roux, B., et al. (2017). Water flux induced reorientation of liquid crystals. ACS central Sci. 3 (12), 1345–1349. doi:10.1021/acscentsci.7b00495

PubMed Abstract | CrossRef Full Text | Google Scholar

Rao, L., Xu, J. H., Cai, B., Liu, H., Li, M., Jia, Y., et al. (2016). Synthetic nanoparticles camouflaged with biomimetic erythrocyte membranes for reduced reticuloendothelial system uptake. Nanotechnology 27 (8), 085106. doi:10.1088/0957-4484/27/8/085106

PubMed Abstract | CrossRef Full Text | Google Scholar

Raucher, D., and Ryu, J. S. (2015). Cell-penetrating peptides: strategies for anticancer treatment. Trends Mol. Med. 21 (9), 560–570. doi:10.1016/j.molmed.2015.06.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Riccio, B. V. F., Silvestre, A. L. P., Meneguin, A. B., Ribeiro, T. C., Klosowski, A. B., Ferrari, P. C., et al. (2022). Exploiting polymeric films as a multipurpose drug delivery system: a review. AAPS PharmSciTech 23 (7), 269. doi:10.1208/s12249-022-02414-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Richards, B., Tsao, D., and Zador, A. (2022). The application of artificial intelligence to biology and neuroscience. Cell 185 (15), 2640–2643. doi:10.1016/j.cell.2022.06.047

PubMed Abstract | CrossRef Full Text | Google Scholar

Rinkevich, Y., Walmsley, G. G., Hu, M. S., Maan, Z. N., Newman, A. M., Drukker, M., et al. (2015). Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Sci. (New York, N.Y.). 348 (6232), aaa2151. doi:10.1126/science.aaa2151

PubMed Abstract | CrossRef Full Text | Google Scholar

Roberts, M., Anderson, R., and Swarbrick, J. (1977). Permeability of human epidermis to phenolic compounds. J. Pharm. Pharmacol. 29 (11), 677–683. doi:10.1111/j.2042-7158.1977.tb11434.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Roberts, M. S., Cheruvu, H. S., Mangion, S. E., Alinaghi, A., Benson, H. A. E., Mohammed, Y., et al. (2021). Topical drug delivery: history, percutaneous absorption, and product development. Adv. drug Deliv. Rev. 177, 113929. doi:10.1016/j.addr.2021.113929

PubMed Abstract | CrossRef Full Text | Google Scholar

Roden, D. M., McLeod, H. L., Relling, M. V., Williams, M. S., Mensah, G. A., Peterson, J. F., et al. (2019). Pharmacogenomics. Lancet. 394 (10197), 521–532. doi:10.1016/s0140-6736(19)31276-0

CrossRef Full Text

Ruseska, I., and Zimmer, A. (2020). Internalization mechanisms of cell-penetrating peptides. Beilstein J. Nanotechnol. 11, 101–123. doi:10.3762/bjnano.11.10

PubMed Abstract | CrossRef Full Text | Google Scholar

Sandri, G., Bonferoni, M. C., Ferrari, F., Rossi, S., and Caramella, C. M. (2014). The role of particle size in drug release and absorption. Part. Prod. Tailoring Prop. Optim. Perform. 2014, 323–341. doi:10.1007/978-3-319-00714-4_11

CrossRef Full Text | Google Scholar

Sato, K., Kang, W. H., Saga, K., and Sato, K. T. (1989). Biology of sweat glands and their disorders. I. Normal sweat gland function. J. Am. Acad. Dermatology 20 (4), 537–563. doi:10.1016/s0190-9622(89)70063-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Schaefer, H., Schalla, W., Zesch, A., and Stüttgen, G. (2013). Skin permeability. Berlin, Germany: Springer Science and Business Media.

Google Scholar

Schärfe, C. P. I., Tremmel, R., Schwab, M., Kohlbacher, O., and Marks, D. S. (2017). Genetic variation in human drug-related genes. Genome Med. 9 (1), 117. doi:10.1186/s13073-017-0502-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Scheuplein, R. J., and Blank, I. H. (1971). Permeability of the skin. Physiol. Rev. 51 (4), 702–747. doi:10.1152/physrev.1971.51.4.702

PubMed Abstract | CrossRef Full Text | Google Scholar

Scheuplein, R. J., Blank, I. H., Brauner, G., and Macfarlane, D. J. (1969). Percutaneous absorption of steroids. J. Investigative Dermatology 52 (1), 63–70. doi:10.1038/jid.1969.9

PubMed Abstract | CrossRef Full Text | Google Scholar

Schneider, P., Walters, W. P., Plowright, A. T., Sieroka, N., Listgarten, J., Goodnow, R. A., et al. (2020). Rethinking drug design in the artificial intelligence era. Nat. Rev. Drug Discov. 19 (5), 353–364. doi:10.1038/s41573-019-0050-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Severn, M. M., and Horswill, A. R. (2023). Staphylococcus epidermidis and its dual lifestyle in skin health and infection. Nat. Rev. Microbiol. 21 (2), 97–111. doi:10.1038/s41579-022-00780-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Shao, H., Im, H., Castro, C. M., Breakefield, X., Weissleder, R., and Lee, H. (2018). New technologies for analysis of extracellular vesicles. Chem. Rev. 118 (4), 1917–1950. doi:10.1021/acs.chemrev.7b00534

PubMed Abstract | CrossRef Full Text | Google Scholar

Shapira, C., Itshak, D., Duadi, H., Harel, Y., Atkins, A., Lipovsky, A., et al. (2022). Noninvasive nanodiamond skin permeation profiling using a phase analysis method: ex vivo experiments. ACS Nano 16 (10), 15760–15769. doi:10.1021/acsnano.2c03613

PubMed Abstract | CrossRef Full Text | Google Scholar

Shen, D., Yang, J., Li, X., Zhou, L., Zhang, R., Li, W., et al. (2014). Biphase stratification approach to three-dimensional dendritic biodegradable mesoporous silica nanospheres. Nano Lett. 14 (2), 923–932. doi:10.1021/nl404316v

PubMed Abstract | CrossRef Full Text | Google Scholar

Shen, H., Aggarwal, N., Wun, K. S., Lee, Y. S., Hwang, I. Y., and Chang, M. W. (2022b). Engineered microbial systems for advanced drug delivery. Adv. drug Deliv. Rev. 187, 114364. doi:10.1016/j.addr.2022.114364

PubMed Abstract | CrossRef Full Text | Google Scholar

Shen, J., Liao, X., Wu, W., Feng, T., Karges, J., Lin, M., et al. (2022a). A pH-responsive iridium (iii) two-photon photosensitizer loaded CaCO 3 nanoplatform for combined Ca 2+ overload and photodynamic therapy. Inorg. Chem. Front. 9, 4171–4183. doi:10.1039/d2qi00951j

CrossRef Full Text | Google Scholar

Shi, C., and Pamer, E. G. (2011). Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11 (11), 762–774. doi:10.1038/nri3070

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, R., Zhou, F., Chen, Y., Liu, Z., Liu, S., and Mu, T. (2022a). Magnetic deep eutectic solvents: formation and properties. Phys. Chem. Chem. Phys. PCCP 24 (34), 20073–20081. doi:10.1039/d2cp01592g

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, V. Y., Leo, M., Hassoun, L., Chahal, D. S., Maibach, H. I., and Sivamani, R. K. (2015). Role of sebaceous glands in inflammatory dermatoses. J. Am. Acad. Dermatology 73 (5), 856–863. doi:10.1016/j.jaad.2015.08.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, Z., Zhao, Y., Liu, S., Wang, Y., and Yu, Q. (2022b). Size-dependent impact of magnetic nanoparticles on growth and sporulation of Aspergillus Niger. Mol. (Basel, Switz. 27 (18), 5840. doi:10.3390/molecules27185840

CrossRef Full Text | Google Scholar

Shibuya, R., Ishida, Y., Hanakawa, S., Kataoka, T. R., Takeuchi, Y., Murata, T., et al. (2021). CCL2‒CCR2 signaling in the skin drives surfactant-induced irritant contact dermatitis through IL-1β‒mediated neutrophil accumulation. J. investigative dermatology 142 (3), 571–582. doi:10.1016/j.jid.2021.07.182

CrossRef Full Text | Google Scholar

Shiekh, A., Mushtaq, A., Jabeen, U., Bashir, F., Zahra, M., Behlil, F., et al. (2022). Surface modification of mesoporous silica nanoparticles with hexamethyl disilazane as smart carriers for tocopherol acetate. Nano Biomed. Eng. 14 (3), 216–224. doi:10.5101/nbe.v14i3.p216-224

CrossRef Full Text | Google Scholar

Shopsowitz, K. E., Roh, Y. H., Deng, Z. J., Morton, S. W., and Hammond, P. T. (2014). RNAi-microsponges form through self-assembly of the organic and inorganic products of transcription. Small (Weinheim der Bergstrasse, Ger. 10 (8), 1623–1633. doi:10.1002/smll.201302676

PubMed Abstract | CrossRef Full Text | Google Scholar

Silva, S., Almeida, A. J., and Vale, N. (2019). Combination of cell-penetrating peptides with nanoparticles for therapeutic application: a review. Biomolecules 9 (1), 22. doi:10.3390/biom9010022

PubMed Abstract | CrossRef Full Text | Google Scholar

Singh, S., and Singh, J. (1993). Transdermal drug delivery by passive diffusion and iontophoresis: a review. Med. Res. Rev. 13 (5), 569–621. doi:10.1002/med.2610130504

PubMed Abstract | CrossRef Full Text | Google Scholar

Song, X., Sun, R., Wang, R., Zhou, K., Xie, R., Lin, J., et al. (2022). Puffball-Inspired microrobotic systems with robust payload, strong protection, and targeted locomotion for on-demand drug delivery. Adv. Mater. Deerf. Beach, Fla.) 34 (43), e2204791. doi:10.1002/adma.202204791

CrossRef Full Text | Google Scholar

Song, Y., Li, D., Lu, Y., Jiang, K., Yang, Y., Xu, Y., et al. (2020). Ferrimagnetic mPEG-b -PHEP copolymer micelles loaded with iron oxide nanocubes and emodin for enhanced magnetic hyperthermia-chemotherapy. Natl. Sci. Rev. 7 (4), 723–736. doi:10.1093/nsr/nwz201

PubMed Abstract | CrossRef Full Text | Google Scholar

Stacy, A., and Belkaid, Y. (2019). Microbial guardians of skin health. Sci. (New York, N.Y.) . 363 (6424), 227–228. doi:10.1126/science.aat4326

PubMed Abstract | CrossRef Full Text | Google Scholar

Stanton, M. M., Park, B. W., Vilela, D., Bente, K., Faivre, D., Sitti, M., et al. (2017). Magnetotactic bacteria powered biohybrids target E. coli biofilms. ACS Nano 11 (10), 9968–9978. doi:10.1021/acsnano.7b04128

PubMed Abstract | CrossRef Full Text | Google Scholar

Starr, N. J., Khan, M. H., Edney, M. K., Trindade, G. F., Kern, S., Pirkl, A., et al. (2022). Elucidating the molecular landscape of the stratum corneum. Proc. Natl. Acad. Sci. U. S. A. 119 (12), e2114380119. doi:10.1073/pnas.2114380119

PubMed Abstract | CrossRef Full Text | Google Scholar

Stoughton, R. B. (1965). Dimethylsulfoxide (DMSO) induction of a steroid reservoir in human skin. Archives dermatology 91, 657–660. doi:10.1001/archderm.1965.01600120089022

PubMed Abstract | CrossRef Full Text | Google Scholar

Sun, F., Zhang, W. B., Mahdavi, A., Arnold, F. H., and Tirrell, D. A. (2014). Synthesis of bioactive protein hydrogels by genetically encoded SpyTag-SpyCatcher chemistry. Proc. Natl. Acad. Sci. U. S. A. 111 (31), 11269–11274. doi:10.1073/pnas.1401291111

PubMed Abstract | CrossRef Full Text | Google Scholar

Sun, Y., Zheng, L., Yang, Y., Qian, X., Fu, T., Li, X., et al. (2020). Metal-organic framework nanocarriers for drug delivery in biomedical applications. Nano-micro Lett. 12 (1), 103. doi:10.1007/s40820-020-00423-3

CrossRef Full Text | Google Scholar

Sweeney, T. M., and Downing, D. T. (1970). The role of lipids in the epidermal barrier to water diffusion. J. Investigative Dermatology 55 (2), 135–140. doi:10.1111/1523-1747.ep12291678

PubMed Abstract | CrossRef Full Text | Google Scholar

Tan, W., Zhang, Q., Quiñones-Frías, M. C., Hsu, A. Y., Zhang, Y., Rodal, A., et al. (2022). Enzyme-responsive peptide thioesters for targeting Golgi apparatus. J. Am. Chem. Soc. 144 (15), 6709–6713. doi:10.1021/jacs.2c02238

PubMed Abstract | CrossRef Full Text | Google Scholar

Tanner, E. E. L., Curreri, A. M., Balkaran, J. P. R., Selig-Wober, N. C., Yang, A. B., Kendig, C., et al. (2019). Design principles of ionic liquids for transdermal drug delivery. Adv. Mater. Deerf. Beach, Fla 31 (27), e1901103. doi:10.1002/adma.201901103

CrossRef Full Text | Google Scholar

Tavares Junior, A. G., de Araújo, J. T. C., Meneguin, A. B., and Chorilli, M. (2022). Characteristics, properties and analytical/bioanalytical methods of 5-aminosalicylic acid: a review. Crit. Rev. Anal. Chem. 52 (5), 1000–1014. doi:10.1080/10408347.2020.1848516

PubMed Abstract | CrossRef Full Text | Google Scholar

Thakkar, S., More, N., Sharma, D., Kapusetti, G., Kalia, K., and Misra, M. (2019). Fast dissolving electrospun polymeric films of anti-diabetic drug repaglinide: formulation and evaluation. Drug Dev. industrial Pharm. 45 (12), 1921–1930. doi:10.1080/03639045.2019.1680994

PubMed Abstract | CrossRef Full Text | Google Scholar

Thyssen, J. P., Godoy-Gijon, E., and Elias, P. M. (2013). Ichthyosis vulgaris: the filaggrin mutation disease. Br. J. dermatology 168 (6), 1155–1166. doi:10.1111/bjd.12219

PubMed Abstract | CrossRef Full Text | Google Scholar

Tian, X., Yang, R., Chen, T., Cao, Y., Deng, H., Zhang, M., et al. (2022). Removal of both anionic and cationic dyes from wastewater using pH-responsive adsorbents of L-lysine molecular-grafted cellulose porous foams. J. Hazard. Mater. 426, 128121. doi:10.1016/j.jhazmat.2021.128121

PubMed Abstract | CrossRef Full Text | Google Scholar

Tiwari, A., Tiwari, V., Palaria, B., Kumar, M., and Kaushik, D. (2022). Microsponges: a breakthrough tool in pharmaceutical research. Future J. Pharm. Sci. 8 (31), 31–25. doi:10.1186/s43094-022-00421-9

CrossRef Full Text | Google Scholar

Toyofuku, M., Nomura, N., and Eberl, L. (2019b). Types and origins of bacterial membrane vesicles. Nat. Rev. Microbiol. 17 (1), 13–24. doi:10.1038/s41579-018-0112-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Thakur, A., Jaiswal, M. K., Peak, C. W., Carrow, J. K., Gentry, J., Dolatshahi-Pirouz, A., et al. (2016). Injectable shear-thinning nanoengineered hydrogels for stem cell delivery. Nanoscale 8 (24), 12362–12372. doi:10.1039/c6nr02299e

PubMed Abstract | CrossRef Full Text | Google Scholar

Trombino, S., Siciliano, C., Procopio, D., Curcio, F., Laganà, A. S., Di Gioia, M. L., et al. (2022). Deep eutectic solvents for improving the solubilization and delivery of dapsone. Pharmaceutics 14 (2), 333. doi:10.3390/pharmaceutics14020333

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsou, P. S., Varga, J., and O'Reilly, S. (2021). Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential. Nat. Rev. Rheumatol. 17 (10), 596–607. doi:10.1038/s41584-021-00683-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Uberoi, A., Bartow-McKenney, C., Zheng, Q., Flowers, L., Campbell, A., Knight, S. A. B., et al. (2021). Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor. Cell host microbe 29 (8), 1235–1248.e8. doi:10.1016/j.chom.2021.05.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Vallet-Regí, M., Schüth, F., Lozano, D., Colilla, M., and Manzano, M. (2022). Engineering mesoporous silica nanoparticles for drug delivery: where are we after two decades? Chem. Soc. Rev. 51 (13), 5365–5451. doi:10.1039/d1cs00659b

PubMed Abstract | CrossRef Full Text | Google Scholar

Walters, K. A. (2002). Dermatological and transdermal formulations. United States: CRC Press.

Google Scholar

Wang, F., Trier, A. M., Li, F., Kim, S., Chen, Z., Chai, J. N., et al. (2021a). A basophil-neuronal axis promotes itch. Cell 184 (2), 422–440.e17. doi:10.1016/j.cell.2020.12.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, G., Sweren, E., Andrews, W., Li, Y., Chen, J., Xue, Y., et al. (2023). Commensal microbiome promotes hair follicle regeneration by inducing keratinocyte HIF-1α signaling and glutamine metabolism. Sci. Adv. 9 (1), eabo7555. doi:10.1126/sciadv.abo7555

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, G., Sweren, E., Liu, H., Wier, E., Alphonse, M. P., Chen, R., et al. (2021b). Bacteria induce skin regeneration via IL-1β signaling. Cell host microbe 29 (5), 777–791.e6. doi:10.1016/j.chom.2021.03.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, H., Alarcón, C. N., Liu, B., Watson, F., Searles, S., Lee, C. K., et al. (2022). Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue. Nat. Biomed. Eng. 6 (7), 882–897. doi:10.1038/s41551-021-00815-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, M., and Phillips, T. D. (2022). Inclusion of montmorillonite clays in environmental barrier formulations to reduce skin exposure to water-soluble chemicals from polluted water. ACS Appl. Mater. Interfaces 14, 23232–23244. doi:10.1021/acsami.2c04676

CrossRef Full Text | Google Scholar

Wang, Y., Li, S., Wang, X., Chen, Q., He, Z., Luo, C., et al. (2021c). Smart transformable nanomedicines for cancer therapy. Biomaterials 271, 120737. doi:10.1016/j.biomaterials.2021.120737

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Z., Wang, F., Zhong, J., Zhu, T., Zheng, Y., Zhao, T., et al. (2020). Using apelin-based synthetic Notch receptors to detect angiogenesis and treat solid tumors. Nat. Commun. 11 (1), 2163. doi:10.1038/s41467-020-15729-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Wegrzyn, A. S., Kedzierska, A. E., and Obojski, A. (2022). Identification and classification of distinct surface markers of T regulatory cells. Front. Immunol. 13, 1055805. doi:10.3389/fimmu.2022.1055805

PubMed Abstract | CrossRef Full Text | Google Scholar

Wickett, R. R., and Visscher, M. O. (2006). Structure and function of the epidermal barrier. Am. J. Infect. control 34 (10), S98–S110. doi:10.1016/j.ajic.2006.05.295

CrossRef Full Text | Google Scholar

Wiedmann, T. S. (1988). Influence of hydration on epidermal tissue. J. Pharm. Sci. 77 (12), 1037–1041. doi:10.1002/jps.2600771210

PubMed Abstract | CrossRef Full Text | Google Scholar

Wigerblad, G., and Kaplan, M. J. (2023). Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases. Nat. Rev. Immunol. 23 (5), 274–288. doi:10.1038/s41577-022-00787-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Wohlrab, J., and Eichner, A. (2023). Supersaturation as a galenic concept for improving the cutaneous bioavailability of drugs in topical therapy. Dermatology Ther. 13 (2), 391–398. doi:10.1007/s13555-022-00873-0

CrossRef Full Text | Google Scholar

Wu, J., Liu, Y., Han, H., and Song, Z. (2023). Recent advances in endogenous and exogenous stimuli-responsive nanoplatforms for bacterial infection treatment. Biomed. Eng. Commun. 2 (1), 2–23. doi:10.53388/bmec2023002

CrossRef Full Text | Google Scholar

Wu, J., Yao, S., Zhang, H., Man, W., Bai, Z., Zhang, F., et al. (2021). Liquid crystal elastomer metamaterials with giant biaxial thermal shrinkage for enhancing skin regeneration. Adv. Mater. Deerf. Beach, Fla 33 (45), e2106175. doi:10.1002/adma.202106175

CrossRef Full Text | Google Scholar

Wu, X., Ju, X., Du, L., Yuan, J., Wang, L., He, R., et al. (2017). Production of bacterial ghosts from gram-positive pathogen Listeria monocytogenes. Foodborne pathogens Dis. 14 (1), 1–7. doi:10.1089/fpd.2016.2184

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, B., Sun, J., and Song, X. (2022a). Hair follicle melanocytes initiate autoimmunity in alopecia areata: a trigger point. Clin. Rev. allergy and Immunol. 63 (3), 417–430. doi:10.1007/s12016-022-08954-w

CrossRef Full Text | Google Scholar

Xie, J., Li, Q., Haesebrouck, F., Van Hoecke, L., and Vandenbroucke, R. E. (2022b). The tremendous biomedical potential of bacterial extracellular vesicles. Trends Biotechnol. 40 (10), 1173–1194. doi:10.1016/j.tibtech.2022.03.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, S., Li, S., Zhang, Z., Chen, M., Ran, P., and Li, X. (2020). Bacterial ghosts for targeting delivery and subsequent responsive release of ciprofloxacin to destruct intracellular bacteria. Chem. Eng. J. 399, 125700. doi:10.1016/j.cej.2020.125700

CrossRef Full Text | Google Scholar

Xie, X., Lei, H., and Fan, D. (2023). Antibacterial hydrogel with pH-responsive microcarriers of slow-release VEGF for bacterial infected wounds repair. J. Mater. Sci. Technol. 144, 198–212. doi:10.1016/j.jmst.2022.09.062

CrossRef Full Text | Google Scholar

Xin, R., Qi, S., Zeng, C., Khan, F. I., Yang, B., and Wang, Y. (2017). A functional natural deep eutectic solvent based on trehalose: structural and physicochemical properties. Food Chem. 217, 560–567. doi:10.1016/j.foodchem.2016.09.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Xu, L., Guo, M., Hung, C. T., Shi, X. L., Yuan, Y., Zhang, X., et al. (2023). Chiral skeletons of mesoporous silica nanospheres to mitigate alzheimer's β-amyloid aggregation. J. Am. Chem. Soc. 145 (14), 7810–7819. doi:10.1021/jacs.2c12214

PubMed Abstract | CrossRef Full Text | Google Scholar

Xu, M., Zhang, J., Mu, Y., Foda, M. F., and Han, H. (2022a). Activation of TRPV1 by capsaicin-loaded CaCO 3 nanoparticle for tumor-specific therapy. Biomaterials 284, 121520. doi:10.1016/j.biomaterials.2022.121520

PubMed Abstract | CrossRef Full Text | Google Scholar

Xu, Z., Chen, D., Hu, Y., Jiang, K., Huang, H., Du, Y., et al. (2022b). Anatomically distinct fibroblast subsets determine skin autoimmune patterns. Nature 601 (7891), 118–124. doi:10.1038/s41586-021-04221-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, D. S., Ghaffari, R., and Rogers, J. A. (2023). Sweat as a diagnostic biofluid. Sci. (New York, N.Y.). 379 (6634), 760–761. doi:10.1126/science.abq5916

CrossRef Full Text | Google Scholar

Yang, J., Yang, Y., Kawazoe, N., and Chen, G. (2019). Encapsulation of individual living cells with enzyme responsive polymer nanoshell. Biomaterials 197, 317–326. doi:10.1016/j.biomaterials.2019.01.029

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, J. A., Kim, E. S., Kwon, J. H., Kim, H., Shin, J. H., Yun, S. H., et al. (2012). Transdermal delivery of hyaluronic acid -- human growth hormone conjugate. Biomaterials 33 (25), 5947–5954. doi:10.1016/j.biomaterials.2012.05.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, R., Wei, T., Goldberg, H., Wang, W., Cullion, K., and Kohane, D. S. (2017). Getting drugs across biological barriers. Adv. Mater. Deerf. Beach, Fla.) 29 (37), 10. doi:10.1002/adma.201606596

CrossRef Full Text | Google Scholar

Yang, Y., Xu, L., Zhu, W., Feng, L., Liu, J., Chen, Q., et al. (2018). One-pot synthesis of pH-responsive charge-switchable PEGylated nanoscale coordination polymers for improved cancer therapy. Biomaterials 156, 121–133. doi:10.1016/j.biomaterials.2017.11.038

PubMed Abstract | CrossRef Full Text | Google Scholar

Yi, X., Wang, H., Yang, Y., Wang, H., Zhang, H., Guo, S., et al. (2023). SIRT7 orchestrates melanoma progression by simultaneously promoting cell survival and immune evasion via UPR activation. Signal Transduct. Target. Ther. 8 (1), 107. doi:10.1038/s41392-023-01314-w

PubMed Abstract | CrossRef Full Text | Google Scholar

Yin, H., Qiu, Z., Zhu, R., Wang, S., Gu, C., Yao, X., et al. (2023). Dysregulated lipidome of sebum in patients with atopic dermatitis. Allergy 78 (6), 1524–1537. doi:10.1111/all.15569

PubMed Abstract | CrossRef Full Text | Google Scholar

You, Y., Tian, Y., Yang, Z., Shi, J., Kwak, K. J., Tong, Y., et al. (2023). Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy. Nat. Biomed. Eng. 7 (7), 887–900. doi:10.1038/s41551-022-00989-w

PubMed Abstract | CrossRef Full Text | Google Scholar

Yu, H., Jacquelot, N., and Belz, G. T. (2022). Metabolic features of innate lymphoid cells. J. Exp. Med. 219 (11), e20221140. doi:10.1084/jem.20221140

PubMed Abstract | CrossRef Full Text | Google Scholar

Zakrewsky, M., Lovejoy, K. S., Kern, T. L., Miller, T. E., Le, V., Nagy, A., et al. (2014). Ionic liquids as a class of materials for transdermal delivery and pathogen neutralization. Proc. Natl. Acad. Sci. U. S. A. 111 (37), 13313–13318. doi:10.1073/pnas.1403995111

PubMed Abstract | CrossRef Full Text | Google Scholar

Zamir, A., Hussain, I., Ur Rehman, A., Ashraf, W., Imran, I., Saeed, H., et al. (2022). Clinical pharmacokinetics of metoprolol: a systematic review. Clin. Pharmacokinet. 61 (8), 1095–1114. doi:10.1007/s40262-022-01145-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, C., Shen, H., Yang, T., Li, T., Liu, X., Wang, J., et al. (2022). A single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma. Nat. Commun. 13 (1), 7250. doi:10.1038/s41467-022-34877-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, H., Jin, Y., Chi, C., Han, G., Jiang, W., Wang, Z., et al. (2021). Sponge particulates for biomedical applications: biofunctionalization, multi-drug shielding, and theranostic applications. Biomaterials 273, 120824. doi:10.1016/j.biomaterials.2021.120824

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, P., Li, Y., Tang, Y., Shen, H., Li, J., Yi, Z., et al. (2020). Copper-based metal-organic framework as a controllable nitric oxide-releasing vehicle for enhanced diabetic wound healing. ACS Appl. Mater. interfaces 12 (16), 18319–18331. doi:10.1021/acsami.0c01792

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, Q., Grice, J. E., Li, P., Jepps, O. G., Wang, G. J., and Roberts, M. S. (2009). Skin solubility determines maximum transepidermal flux for similar size molecules. Pharm. Res. 26 (8), 1974–1985. doi:10.1007/s11095-009-9912-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, Q., Vigier, K. D. O., Royer, S., and Jérôme, F. (2012). Deep eutectic solvents: syntheses, properties and applications. Chem. Soc. Rev. 41 (21), 7108–7146. doi:10.1039/c2cs35178a

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, W., Gao, Y., Xue, R., Nguyen, W., Chen, W., Wang, J., et al. (2023). Liquid formulations based on ionic liquids in biomedicine. Mater. Today Phys. 30 (3), 100925. doi:10.1016/j.mtphys.2022.100925

CrossRef Full Text | Google Scholar

Zhao, H., Shu, G., Zhu, J., Fu, Y., Gu, Z., and Yang, D. (2019). Persistent luminescent metal-organic frameworks with long-lasting near infrared emission for tumor site activated imaging and drug delivery. Biomaterials 217, 119332. doi:10.1016/j.biomaterials.2019.119332

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhao, Z., Li, M., Zheng, L., Yang, Y., Cui, X., Xu, T., et al. (2022). Noninvasive transdermal delivery of mesoporous silica nanoparticles using deep eutectic solvent. J. Control. release official J. Control. Release Soc. 343, 43–56. doi:10.1016/j.jconrel.2022.01.019

CrossRef Full Text | Google Scholar

Zheng, H. L., and Zhang, Y. C. (2017). Elementary analysis on external treatment in Li Yue pian wen. J. Clin. Acupunct. Moxibustion 33 (5), 78–80.

CrossRef Full Text | Google Scholar

Zheng, Y., Hunt, R. L., Villaruz, A. E., Fisher, E. L., Liu, R., Liu, Q., et al. (2022). Commensal Staphylococcus epidermidis contributes to skin barrier homeostasis by generating protective ceramides. Cell host microbe 30 (3), 301–313.e9. doi:10.1016/j.chom.2022.01.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, H., Tan, X., Chen, G., Liu, X., Feng, A., Liu, Z., et al. (2023). Extracellular vesicles of commensal skin microbiota alleviate cutaneous inflammation in atopic dermatitis mouse model by Re-establishing skin homeostasis. J. investigative dermatology. doi:10.1016/j.jid.2023.02.023

CrossRef Full Text | Google Scholar

Zhou, J., Lin, Z., Penna, M., Pan, S., Ju, Y., Li, S., et al. (2020b). Particle engineering enabled by polyphenol-mediated supramolecular networks. Nat. Commun. 11 (1), 4804. doi:10.1038/s41467-020-18589-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, J., Shi, D., and Chen, M. (2020a). Bio-inspired mineral fluorescent hydrogels cross-linked by amorphous rare earth carbonates. Chem. Commun. Camb. Engl. 56 (88), 13646–13648. doi:10.1039/d0cc06223e

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, L., Lin, Q., and Sonnenberg, G. F. (2022b). Metabolic control of innate lymphoid cells in health and disease. Nat. Metab. 4 (12), 1650–1659. doi:10.1038/s42255-022-00685-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, Q., Si, Z., Wang, K., Li, K., Hong, W., Zhang, Y., et al. (2022a). Enzyme-triggered smart antimicrobial drug release systems against bacterial infections. J. Control. release official J. Control. Release Soc. 352, 507–526. doi:10.1016/j.jconrel.2022.10.038

CrossRef Full Text | Google Scholar

Zhou, S., Zhong, Q., Wang, Y., Hu, P., Zhong, W., Huang, C. B., et al. (2022c). Chemically engineered mesoporous silica nanoparticles-based intelligent delivery systems for theranostic applications in multiple cancerous/non-cancerous diseases. Coord. Chem. Rev. 452, 214309. doi:10.1016/j.ccr.2021.214309

CrossRef Full Text | Google Scholar

Zhou, X., Chen, Y., Cui, L., Shi, Y., and Guo, C. (2022d). Advances in the pathogenesis of psoriasis: from keratinocyte perspective. Cell death Dis. 13 (1), 81. doi:10.1038/s41419-022-04523-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu, L. (2007). Examination and interpretation of the formulas for fifty-two diseases. J. Chin. Med. Mater., 1613–1615. doi:10.3321/j.issn:1001-4454.2007.12.044

CrossRef Full Text | Google Scholar

Zhu, Y., Yang, Z., Dong, Z., Gong, Y., Hao, Y., Tian, L., et al. (2020). CaCO 3 -assisted preparation of pH-responsive immune-modulating nanoparticles for augmented chemo-immunotherapy. Nano-micro Lett. 13 (1), 29. doi:10.1007/s40820-020-00549-4

CrossRef Full Text | Google Scholar

Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R., and Goodman, A. L. (2019a). Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 570 (7762), 462–467. doi:10.1038/s41586-019-1291-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R., and Goodman, A. L. (2019b). Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science 363 (6427), eaat9931. doi:10.1126/science.aat9931

PubMed Abstract | CrossRef Full Text | Google Scholar

Zouboulis, C. C., Coenye, T., He, L., Kabashima, K., Kobayashi, T., Niemann, C., et al. (2022). Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations. Front. Immunol. 13, 1029818. doi:10.3389/fimmu.2022.1029818

PubMed Abstract | CrossRef Full Text | Google Scholar

Zuo, Y. M., Yan, X., Xue, J., Guo, L. Y., Fang, W. W., Sun, T. C., et al. (2020). Enzyme-responsive Ag nanoparticle assemblies in targeting antibacterial against methicillin-resistant Staphylococcus aureus. ACS Appl. Mater. interfaces 12 (4), 4333–4342. doi:10.1021/acsami.9b22001

PubMed Abstract | CrossRef Full Text | Google Scholar

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