Metabolic engineering of adipose‐derived stem cell exosomes via arachidonic acid potentiates diabetic wound repair by orchestrating angiogenesis: A multi‐omics guided strategy

Abstract Diabetic wounds are common and challenging complications of diabetes, characterized by delayed healing and an increased risk of infection. Exosomes derived from adipose‐derived stem cells (ADSCs) represent cell‐free therapeutic agents and are potential candidate drugs for treating diabetic wound healing. Our pre‐experimental and metabolomic analyses suggest that arachidonic acid (AA) metabolism can effectively promote wound healing in diabetic animal models. Exosomes from ADSCs pretreated with arachidonic acid (AA‐Exos) markedly improved the viability and proliferation of human umbilical vein endothelial cells under high glucose stress conditions, while also enhancing their biological functions, such as cell migration, angiogenesis, wound repair, and vascular endothelial growth factor (VEGF) expression. This study aimed to investigate the effect of AA‐Exos on the healing of diabetic wounds. Proteomic and transcriptomic analyses, along with pathway activation studies, revealed that AA‐Exos promoted angiogenesis by activating the PI3K/AKT/mTOR signaling pathway. In vivo experiments demonstrated that diabetic mice treated with AA‐Exos exhibited accelerated wound healing and increased vascularization. In addition, the compound stimulated collagen deposition and boosted VEGF and CD31 expression, indicating robust angiogenesis during diabetic wound healing. This study provides a novel perspective on exosome therapy for wound healing and effectively improves the therapeutic effects of exosomes.