A multifunctional hydrogel loaded with magnesium-doped bioactive glass-induced vesicle clusters enhances diabetic wound healing by promoting intracellular delivery of extracellular vesicles

The treatment of diabetic wounds (DWs) poses a significant medical challenge. Mesenchymal stem cell-derived small extracellular vesicles (sEVs) have demonstrated potential in accelerating healing by delivering growth factors and microRNAs. However, the rapid clearance by the circulatory system limits their concentration and bioavailability within cells. This study employed magnesium-doped bioactive glass (MgBG) to autonomously program sEVs into a vesicle cluster (EPPM), which was subsequently incorporated into a hydrogel to create a comprehensive repair system that enhanced the delivery of both sEVs and MgBG, thereby promoting rapid healing of diabetic wounds. This hydrogel exhibited excellent injectable, self-healing and bioadhesive properties, making it an ideal physical barrier for DWs. In addition, the hydrogels also possessed photoresponsive properties that facilitated their bactericidal activity. The released EPPM significantly increased the intracellular uptake and accumulation of sEVs, with approximately 8.2-fold enhancement in macrophages and 16.7-fold in endothelial cells. The EPPM clusters efficiently induce macrophage M2 polarization, reduce inflammatory responses at the wound site, and recruit cells, thereby promoting angiogenesis and collagen deposition. This integrated repair system provided a new platform for the comprehensive treatment of diabetic wounds. • sEVs was autonomously programmed into vesicle clusters using MgBG to enhance the delivery of sEVs and MgBG. • EPPM clusters efficiently induced macrophage M2 polarization, reduced inflammatory responses and recruited stem cells. • The hydrogel exhibited excellent injectable, self-healing and bioadhesive properties. • This integrated repair system provided a new platform for the comprehensive treatment of diabetic wounds.