Extracellular Matrix-Mimicking Hydrogel with Angiogenic and Immunomodulatory Properties Accelerates Healing of Diabetic Wounds by Promoting Autophagy

The management of diabetic wounds faces significant challenges due to the excessive activation of reactive oxygen species (ROS), dysregulation of the inflammatory response, and impaired angiogenesis. A substantial body of evidence suggests that the aforementioned diverse factors contributing to the delayed healing of diabetic wounds may be associated with impaired autophagy. Impaired autophagy leads to endothelial and fibroblast dysfunction and impedes macrophage phenotypic transformation. This disruption hinders angiogenesis and extracellular matrix deposition, ultimately culminating in delayed wound healing. Therefore, biomaterials possessing autophagy regulatory functions hold significant potential for clinical applications in enhancing the healing of diabetic wounds. A hybrid multifunctional hydrogel (GelMa@SIS-Qu) has been developed, comprising methacrylamide gelatin (GelMa), a small intestine submucosal acellular matrix (SIS), and quercetin nanoparticles, which demonstrates the capability to promote autophagy. The promotion of autophagy not only reduces ROS levels in endothelial cells and enhances their antioxidant activity but also mitigates ROS-induced endothelial cell dysfunction and apoptosis, thereby promoting angiogenesis. Furthermore, the promotion of autophagy facilitates the phenotypic transformation of macrophages from the M1 phenotype to the M2 phenotype. This study investigates the distinctive mechanisms of the GelMa@SIS-Qu hydrogel and proposes a promising therapeutic strategy for treating diabetes-related wounds.