Alfredo Maria Gravagnuolo ^1* Alessandro Martucci ^2* Eden Morales-Narváez ^3*

• ¹ The Nanobiotechnology Hub, Cambridge, United Kingdom
• ² Department of Industrial Engineering, School of Engineering, University of Padua, Padua, Veneto, Italy
• ³ Biophotonic Nanosensors Laboratory, Centro de Física Aplicada y TecnologíaAvanzada (CFATA), Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico

What does the future hold for two-dimensional (2D) materials? The future is the combination of biotechnology and nanotechnology. The potential applications of nanotechnology in the areas of healthcare and biomedicine are endless. Biological interfacing of 2D materials is a key step towards this paradigm.Graphene is the first 2D material isolated, studied and produced of the history, although Sir. Andre Geim acknowledged some early ideas belonging to graphene "pre-history" (Geim, 2012). Today, after the 20 th anniversary of its first characterization, graphene technology is not in its infancy any longer. The impact of research on the innovations, industrialization and commercialization is tangible right now, as proven by the variety of successful patents, commercial spin-offs and start-ups, and products. Some recently published and upcoming ISO standards, (ISO/TR 19733, 2019; ISO/TS 21356-1, 2021; ISO/TS 80004-13, 2024; ISO/AWI TS 21356-2, New project approved; ISO/DTS 23359, in the approval phase) are designed to boost the deployment of graphene technology. This is particularly necessary to introduce graphene in the highly regulated markets of products that come in direct contact with human, and to assess the environmental impact of generated waste. Standardized production processes, systematic structural assessment of graphene forms, and specific nomenclature for each member of the graphene family, will in turn facilitate the assessment of structure-properties, structure-safety relationships and market approvals by regulatory agencies.In this perspective, recent human clinical trials, (ID NCT03659864 -University of Edinburgh, 2024; ID NCT06368310 David Coope, Northern Care Alliance NHS Foundation Trust, 2024) intend to unleash a new era of graphene in healthcare applications (Andrews et al., 2024). In the current landscape of clinical translation, human clinical trials, which ensure rigorous toxicology investigation, performed in highly regulated setting, will build up robust and reliable toxicology data sets as fundaments for future uses in the main themes of biotechnology and medicine: (a) diagnostics, biosensing and imaging; (b) neural interfaces, prosthetic implants and other implantable devices; (c) cancer therapy and drug/gene delivery systems; (d) Tissue engineering and regenerative medicine (albeit this is a cross-functional theme with b and c); (e) antimicrobial and antiviral; (f) industrial bioprocesses, bioreactors and other nano-bio devices.This editorial project started in 2019 with Vol I (hyperlink: https://www.frontiersin.org/researchtopics/10687/biointerfacing-2d-nanomaterials-and-engineered-heterostructures/articles), aims to track advances in the most innovative fields of application of 2D nanomaterials, from graphene to the whole family of novel 2D materials, and their engineered heterostructures, which entails a deep understanding of phenomena happening upon biointerfacing. Graphene has proven ideal for neural interface applications, due to its remarkable electrical and mechanical properties, for stimulation and sensing, and high specific surface area for functionalization and cell bio interfacing. Ongoing clinical trials are investigating their functionality and side effects, to assess benefit-risk ratios associated with brain mapping in applications such as cancer brain surgery and treatment of Parkinson disease (ID NCT06368310 David Coope, Northern Care Alliance NHS Foundation Trust, 2024).In this article collection, the comprehensive review titled "Graphene-Based Nanomaterials (GBMs) for Peripheral Nerve Regeneration" (Convertino D et al. Hiperlink: https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1306184/full), considers the exploitation of GBMs biointerfaced, not only with the central nervous system (CNS), but above all with cells associated with peripheral nervous system (PNS), whose ever-increasing attention is being devoted. After describing the development of several graphene production methods, forms (e.g. 3D scaffolds, or conductive coatings) and formulations for nerve repair, the authors critically reviewed graphene interaction with peripheral neurons and, remarkably, highlighted the critical aspect of the local impact of non-neuronal cell alterations induced by the material on nerve regeneration. This no neuro-centric approach is quite broad-minded and highlights the need for a synergic contribution of many cell phenotypes to orchestrate a neuro-regenerative process, laying the foundational evidence of GBM safety and biocompatibility, which is a crucial aspect for clinical translation. Novel 2D materials, showing a full palette of physicochemical properties, are under the research spotlight. When assembled in Van der Waals vertical heterostructures, nanocomposites or other nanoassemblies not existing in the nature, they display exotic phenomena. Available in different forms such as powders, liquid dispersions, membranes and surface coatings, polymer nanocomposites and hydrogels, foams and aerogels, they virtually find application in any field. Biological interactions with biomolecules and living systems introduce the next functional dimensions. This article collection highlights the significant potential of 2D layered materials and engineered heterostructures for therapy and diagnostics with three articles in the context of phototherapy and cancer theragnostics. A lesson learned in the Vol II of this article collection is that, whilst graphene has reached a mature stage towards clinical translation, it has also paved the way to a plethora of new 2D materials and heterostructures, which will follow in the upcoming years. Insisting on systematic physicochemical characterization, classification and toxicological evaluation is the key for the deployment of potentially endless technologies enabled by 2D materials and evaluation of risk-benefit ratio in each application.