Mitochondrial biogenesis modulation by silicon-stimulated mesenchymal stem cells-derived extracellular vesicles drives angio- and lymphangiogenesis in chronic wound healing.

Diabetic wounds are characterized by chronic inflammation, reduced angiogenesis, and insufficient collagen deposition, leading to impaired healing. Extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSC) offer a promising cell-free therapeutic strategy; however, their efficacy and immunomodulation can be enhanced through bioactivation. In this study, we incorporated calcium silicate-stimulated ADSC-derived EVs (CSEVs) into collagen hydrogels to create a sustained-release system to promote diabetic wound healing. CSEVs exhibit enhanced protein content, surface marker expression, and bioactive cargo enriched with proangiogenic and anti-inflammatory factors. In addition, the suppression of proinflammatory signaling, polarization of M2 macrophages, stimulation of angiogenesis and lymphangiogenesis, and activation of mitochondrial function in dermal fibroblasts were among the many effects of CSEVs on the wound microenvironment. Moreover, miR-31 in CSEVs demonstrated an important factor in promoting difficult wound repair. These results highlight the potential of collagen scaffolds incorporated with CSEVs as strong acellular substrates for improving wound healing in diabetic environments. CSEVs and miRNA-mediated cues work together to overcome regeneration constraints of chronic wounds.