MiR-486-5p-modified sEVs encapsulated in GelMA hydrogel facilitated wound healing by targeting Smurf2/TGF-β1 pathways

Sustained delivery of therapeutic agents such as small extracellular vesicles (sEVs) in biomaterial scaffolds is expected to bring new hope for chronic wound treatment. Although sEVs derived from mesenchymal stem cells (MSCs) have been demonstrated to promote wound healing, there are still challenges associated with inadequate angiogenesis, poor localization, and consequently suboptimal outcomes. Herein, we derived small extracellular vesicles (sEVs) from dental pulp stem cells (DPSCs) overexpressing miR-486-5p (sEV-486-5p) and encapsulated them in gelatin methacryloyl (GelMA) hydrogel for wound treatment. In this study, the sEVs derived from miR-486-5p overexpressing DPSCs (sEV-486-5p) with a ~14-fold increase in expression of miR-486-5p were found to improve angiogenic activities of human umbilical vein endothelial cells (HUVECs) in vitro . Further bioinformatics prediction and dual-luciferase reporter assay verified the binding between miR-486-5p and Smad ubiquitination regulatory factor 2 (Smurf2). Mechanistically, sEV-486-5ppromoted the angiogenic properties of HUVECs by increasing the TGF-β1 protein expression and Smad2 phosphorylation, while decreasing the Smurf2 expression. Upon knockdown of Smurf2, the angiogenic activities of HUVECs were enhanced. Inhibition of TGF-β1/Smad2 pathway using SB431542 also suppressed angiogenesis induced by sEV-486-5p. sEV-486-5p encapsulated in GelMA hydrogel exhibited sustained release and accelerated wound healing by enhancing angiogenesis. Overall, GelMA hydrogel encapsulating sEV-486-5p can promote wound healing through miR-486-5p-mediated angiogenesis, thus representing an innovative approach for wound management.