2A-biohydrogels accelerate diabetic wound healing by promoting M2 macrophage polarization and functionalized mitochondrial transfer to endothelial cells

Diabetic chronic wounds pose a significant clinical challenge due to their complex pathophysiology and limited treatment options. In this study, a silk fibroin/gelatin (SG) gel incorporated with Mdivi-1 (SG/M) was developed and applied to chronic diabetic wounds. The SG/M hydrogel significantly enhanced diabetic wound healing compared to the plain SG hydrogel. This potential therapeutic potential of Mdivi-1 relies on promoting macrophage polarization toward the M2 phenotype and restoring hyperglycemia-mediated mitochondrial dynamic disorders and dysfunction in both macrophages and human umbilical vein endothelial cells (HUVECs) under high glucose conditions. Furthermore, Mdivi-1 facilitated mitochondrial transfer from macrophages to HUVECs, which further enhanced mitochondrial function in HUVECs and improved their cellular activity. These findings not only establish Mdivi-1 as a potential novel therapy but also provide a theoretical foundation for targeting diabetic complications, underscoring the originality and clinical relevance of this research.