GelMA hydrogel enhances diabetic wound healing by delivering shock wave-preconditioned BMSC-derived small extracellular vesicles

Introduction Diabetic foot ulcers (DFUs) are chronic, hard-to-heal wounds characterized by impaired angiogenesis, persistent inflammation, and defective extracellular matrix remodeling. Bone marrow mesenchymal stem cell-derived small extracellular vesicles (BMSC-sEVs) hold promise for cell-free therapy; however, their therapeutic efficacy is limited by insufficient reparative bioactivity and rapid local clearance. This study aimed to enhance the intrinsic therapeutic potential of BMSC-sEVs through shock wave preconditioning and improve their local retention and sustained delivery using gelatin methacryloyl (GelMA) hydrogel. Methods BMSCs were preconditioned with shock waves, and the resulting small extracellular vesicles (SW-sEVs) were isolated and characterized. Their angiogenic and immunomodulatory effects were evaluated using human umbilical vein endothelial cells (HUVECs) and RAW264.7 macrophages. Proteomic analysis and Western blotting were performed to investigate potential underlying mechanisms. SW-sEVs were subsequently incorporated into a 15% GelMA hydrogel, and the resulting delivery system was characterized. Its therapeutic efficacy was evaluated in a streptozotocin (STZ)-induced hyperglycemic rat wound model. Results Shock wave preconditioning did not alter the typical morphology, particle size distribution, or marker protein expression of BMSC-sEVs. Compared with sEVs derived from untreated BMSCs, SW-sEVs significantly enhanced HUVEC proliferation, migration, and tube formation, accompanied by increased VEGFA and CD31 expression. SW-sEVs also suppressed pro-inflammatory macrophage activation, promoted a reparative macrophage phenotype, and reduced the expression of pro-inflammatory factors. Proteomic analysis revealed alterations in sEV protein cargo, with differentially expressed proteins enriched in inflammation-related pathways, including NF-κB signaling. Western blotting further demonstrated reduced phosphorylation of p65 and IκBα following SW-sEV treatment. The 15% GelMA hydrogel exhibited an interconnected porous structure, favorable cytocompatibility, structural stability, and sustained SW-sEV release. In vivo, GelMA-SW-sEVs significantly accelerated diabetic wound healing, enhanced neovascularization and M2 macrophage polarization, reduced local inflammation, and improved re-epithelialization, collagen deposition, and tissue remodeling. Discussion Shock wave preconditioning enhances the angiogenic and immunomodulatory activities of BMSC-sEVs, potentially through modulation of NF-κB-related inflammatory signaling. Combined with sustained local delivery using GelMA hydrogel, SW-sEVs demonstrate promising therapeutic potential as a cell-free strategy for diabetic wound repair.