Astragaloside IV and Ferulic Acid Loaded iRGD ‐Modified Liposomes Promote Diabetic Wound Healing by Suppressing H4K12

ABSTRACT

Impaired wound healing is a severe complication of diabetes and is partly attributable to endothelial progenitor cell (EPC) dysfunction. Although liposomal delivery has attracted increasing interest in diabetic wound therapy, EPC‐targeted delivery strategies remain insufficiently defined. In this study, internalizing RGD (iRGD)‐modified liposomes co‐loaded with astragaloside IV and ferulic acid (Lp‐iRGD@AS‐IV/FA) were prepared by thin‐film hydration. Lp‐iRGD@AS‐IV/FA showed favorable sustained‐release behavior and enhanced uptake by EPCs. In a diabetic mouse wound model induced by a high‐fat diet and streptozotocin, Lp‐iRGD@AS‐IV/FA accelerated wound closure, improved epithelial architecture, reduced inflammatory infiltration, and increased collagen deposition. In bone marrow‐derived EPCs exposed to high glucose, Lp‐iRGD@AS‐IV/FA restored proliferation, migration, and tube formation, reduced lactate accumulation and histone lactylation, and alleviated mitochondrial dysfunction. Mechanistically, inhibition of lactate production by Oxamate decreased histone H4 lysine 12 lactylation (H4K12 la) and Forkhead Box O1 (FOXO1) expression, reduced H4K12la enrichment at the FOXO1 promoter, and suppressed FOXO1 promoter activity. Conversely, FOXO1 overexpression attenuated the protective effects of Lp‐iRGD@AS‐IV/FA on EPC function. These findings indicate that Lp‐iRGD@AS‐IV/FA promotes diabetic wound healing by suppressing H4K12la‐mediated FOXO1 transcriptional activation and support EPC‐targeted nanodelivery as a potential therapeutic strategy for diabetic wound repair.