Ellagic Acid‐Loaded <scp>sEVs</scp> Encapsulated in <scp>GelMA</scp> Hydrogel Accelerate Diabetic Wound Healing by Activating <scp>EGFR</scp> on Skin Repair Cells

Delayed diabetic wound healing is partially attributed to the functional disorder of skin repair cells caused by high glucose (HG). Small extracellular vehicles (sEVs) loaded with small-molecule drugs represent a highly promising therapeutic strategy. This study aims to evaluate the therapeutic efficacy of ellagic acid-encapsulated small extracellular vesicles (EA-sEVs) in diabetic wound regeneration and to unravel related mechanisms. Cytotoxicity tests of ellagic acid (EA) as liposomal small molecules (LSMs) were performed with the CCK8 assay. EA was incorporated into sEVs obtained from chorionic plate-mesenchymal stem cells (CP-MSCs) to construct EA-engineered sEVs. The protective effects of EA-sEVs on human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) induced by high glucose (HG) were assessed through the evaluation of their proliferative, migrative and differentiative capabilities. Furthermore, to illustrate the underlying mechanism, the specific biological targets of EA were predicted and confirmed. Finally, EA-sEVs were encapsulated in GelMA hydrogel for investigating the pro-healing effects on diabetic wounds. EA was harmless to cell viability, increasing the possibility and safety of drug development. EA-engineered sEVs were fabricated by loading EA in sEVs. In vitro, EA-sEVs promoted the proliferation, migration, and transdifferentiation of HG-HDFs and the proliferation and migration of HG-HEKs. Mechanism analysis elucidated that epidermal growth factor receptor (EGFR) was the specific biological target of EA. EA interacting with EGFR was responsible for the functional improvement of HG-HDFs and HG-HEKs. In vivo, EA-sEVs encapsulated in GelMA promoted the healing of diabetic wounds by improving re-epithelialisation, collagen formation and the expression of EGFR. Gel-EA-sEVs promoted diabetic wound healing by improving biological functions of HDFs and HEKs. EGFR was first identified as the specific biological target of EA and was responsible for the functional improvement of HG-HDFs and HG-HEKs by Gel-EA-sEVs. Hence, Gel-EA-sEVs can serve as a new promising active dressing for diabetic wound treatment.