Marwa Ibrahim Abd El-Hamid ¹ Ahmed Abdelfattah-Hassan ² Osama B Mohammed ³ Ioan Pet ⁴ Samah S Khalil ⁵ Sara Taha Elazab ⁶ Aya S M Metwally ⁷ Leena Alqahtani ⁸ Asmaa A Azouz ⁹ Ahmed A Elnegiry ¹⁰ Shimaa S Elnahriry ¹¹ Mirela Ahmadi ⁴ Doaa Ibrahim ^12*

• ¹ Department of Microbiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt, Zagazig, Wallis and Futuna
• ² Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, October Gardens, 6th of October, Giza 12578, Egypt, Zagazig, Egypt
• ³ Department of Zoology, College of Science, King Saudi University, Riyadh 11451, Saudi Arabia, Riyadh, Saudi Arabia
• ⁴ Department of Biotechnology, Faculty of Bioengineering of Animals Resources, University of Life Sciences “King Mihai I” from Timisoara, 300645 Timisoara, Romania, Timisoara, Romania
• ⁵ Department of Biochemistry& molecular biochemistry, Drug Information Centre, Zagazig University Hospitals, Zagazig University, Egypt, Zagazig, Egypt
• ⁶ Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt, mansoura, Egypt
• ⁷ Department of Pharmacology, Faculty of Veterinary Medicine, Aswan University, Egypt, aswan, Egypt
• ⁸ Department of Biochemistry, Faculty Of science, university of Jeddah, Jeddah 80203, Saudi Arabia, jeddah, Saudi Arabia
• ⁹ Department of pharmacology, faculty of veterinary Medicine, Cairo university, Giza, Egypt, cairo, Egypt
• ¹⁰ Department of Cytology and Histology, Faculty of Veterinary Medicine, Aswan University, Aswan, Egypt, aswan, Egypt
• ¹¹ Department of Bacteriology, Mycology and Immunology, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt, Sadat, Egypt
• ¹² Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt

Smart innovative nanocomposites based on active ingredients and metallic nanoparticles with effective wound healing and antifungal properties are efficient in overcoming limitations of traditional therapeutic products. Open wounds providing an ideal niche for colonization by Candida albicans (C. albicans) pose substantial global health issues owing to delayed wound healing and disordered healing mechanisms. Therefore, innovative proficient therapies controlling C. albicans infections as well as promoting wound healing are of imperative importance for management of wounds and prevention of infection and possible complications. This study aims to design a novel nanocarrier platform based on silver nanoparticles (AgNPs) loaded hydrogel doped with pomegranate peel extract (PPE) and hyaluronic acid (HA) offering an unprecedented opportunity to achieve skin repair and manage C. albicans colonization with an efficient wound healing process. Sprague-Dawley rats (n=100) assigned to 5 groups were infected with C. albicans and distributed as follows: control positive (untreated) and four cutaneous wound-healing model groups treated topically with commercial cream and PPE-HA-AgNPs at full, 50% and 25% concentrations for 15 days. Our findings revealed that clinical signs severity, C. albicans burden as well expression of biofilm related genes; ALS1, HYR1and PLB1 were diminished following treatment with PPE-HA-AgNPsIII. Notably, formulated nanocomposite was very effective in extending the release of PPE-HA-AgNPs in infected wounds with retention percentages of 65.4% for PPE-HA-AgNPsIII. Topical administration of PPE-HA-AgNPsIII successfully alleviated extensive inflammatory response along with wounded skin via down streaming of TNF-α, IL-6 and IL-1 beta, and NOS levels using ELISA and RT-qPCR assays. Interestingly, PPE-HA-AgNPsIII modulated angiogenic and wound healing markers as evidenced by downregulation of MMP-9 and upregulation of Ang-1 and VEGF (up to 10 days post-treatment) and TGF-β1, bFGF, EGF, Ki-67 and collagen I and III with an efficient wound closure capability. It was evidenced by lessening its histopathological picture severity, which accelerated the healing of infected skin wounds post-treatment with PPE-HA-AgNPs. Overall, our formulated PPE-HA-AgNPs provide an innovative therapeutic effective strategy for the treatment of cutaneous wounds infected with C. albicans with maximize wound healing efficacy recommending their potential in clinical practice