Nanoscale Systems for Local Activation of Hypoxia-Inducible Factor-1 Alpha: A New Approach in Diabetic Wound Management

Sameh Saber,1 Rasha Abdelhady,2 Mai A Elhemely,3,4 Elsayed A Elmorsy,5 Rabab S Hamad,6 Mustafa Ahmed Abdel-Reheim,4,7 Attalla F El-kott,8 Mohammed A AlShehri,8 Kareem Morsy,8 Sally Negm,9 Ahmed Y Kira10 1Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; 2Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, 63514, Egypt; 3School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M20 4BX, UK; 4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, 62521, Egypt; 5Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, 51452, Saudi Arabia; 6Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia; 7Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia; 8Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia; 9Department of Life Sciences, College of Science and Art Mahyel Aseer, King Khalid University, Abha, 62529, Saudi Arabia; 10Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, EgyptCorrespondence: Mustafa Ahmed Abdel-Reheim; Ahmed Y Kira, Department of Pharmaceutics, Faculty of Pharmacy, ‎Delta University for Science and Technology, Gamasa, 11152, Egypt, Tel +2 1026462867, Fax +2 502770140, Email [email protected]; [email protected]: Chronic wounds in diabetic patients experience significant clinical challenges due to compromised healing processes. Hypoxia-inducible factor-1 alpha (HIF-1α) is a critical regulator in the cellular response to hypoxia, enhancing angiogenesis and tissue restoration. Nevertheless, the cellular response to the developed chronic hypoxia within diabetes is impaired, likely due to the destabilization of HIF-1α via degradation by prolyl hydroxylase domain (PHD) enzymes. Researchers have extensively explored HIF-1α activation as a potential pathway for diabetic wound management, focusing mainly on deferoxamine (DFO) as a potent agent to stabilize HIF-1α. This review provides an update of the other recent pharmacological agents managing HIF-1α activation, including novel PHD inhibitors (roxadustat and daprodustat) and Von Hippel‐Lindau protein (VHL) antagonists, which could be potential alternatives for the local treatment of diabetic wounds. Furthermore, it highlights how localized delivery via advanced nanostructures can enhance the efficacy of these novel therapies. Importantly, by addressing these points, the current review can offer a promising area for research. Given that, these novel drugs have minimal applications in diabetic wound healing, particularly in the context of local application through nanomaterials. This gap presents an exciting opportunity for further investigation, as combining these drugs with localized nanotechnology could avoid undesired systemic side effects and sustain drug release within wound site, offering a transformative platform for diabetes wound treatment. Keywords: nanomedicine, localized delivery, diabetic wound healing, novel prolyl hydroxylase inhibitors