Chronic nonhealing wounds are major complications in diabetic patients, with impaired angiogenesis playing a critical role in the delayed healing process. Current treatments for diabetic wounds are inadequate. The dysregulation of endothelial cell genes, particularly thrombospondin-1 (TSP-1), impairs neovascularization and delays wound repair. In recent years, hydrogel-based wound dressings have gained widespread application in biomedicine. The study introduced a new therapeutic approach, embedding miR-221-3p-loaded small extracellular vesicles (miR-221^OE-sEVs) within gelatin methacryloyl (GelMA) hydrogels to reduce TSP-1 levels and improve healing in diabetic wounds.

First, we observed upregulated TSP-1 expression in human umbilical vein endothelial cells (HUVECs) when cultured in a high-glucose (HG) environment. We employed small interfering RNA (siRNA) and miR-221-3p to suppress TSP-1 expression and then evaluate the functional effects on HUVECs. Subsequently, miR-221-3p was encapsulated in sEVs via lentiviral transfection. The effects of miR-221^OE-sEVs on HUVECs under HG conditions were evaluated. Finally, miR-221^OE-sEVs were incorporated into a GelMA hydrogel (G-miR-221^OE-sEVs) and applied to a diabetic murine wound model to evaluate their effects on wound closure and angiogenesis.

Under HG conditions, the use of siTSP-1 to silence TSP-1 enhanced the proliferation, migration, and tube formation capabilities of HUVECs. Similarly, miR-221-3p treatment exerted proregenerative effects via the targeting of TSP-1. We successfully generated miR-221^OE-sEVs that exhibited a 28-fold increase in miR-221-3p expression, which significantly enhanced HUVEC functionality under HG conditions. Encapsulation within the GelMA hydrogel enabled G-miR-221^OE-sEVs to significantly accelerate diabetic wound healing via increased angiogenesis.

This study demonstrated the successful fabrication of a novel bioactive wound dressing (G-miR-221^OE-sEVs), which promotes diabetic wound healing by promoting angiogenesis through the regulation of TSP-1. This approach offers a potential therapeutic option for enhancing the management of diabetic wounds.