Engineered Exosomes Loaded in Intrinsic Immunomodulatory Hydrogels with Promoting Angiogenesis for Programmed Therapy of Diabetic Wounds

Inducing rapid angiogenesis by delivering specific biological cues is critical for diabetic wound healing. Nevertheless, the angiogenesis is hindered by the inflammatory microenvironment, and the immune cells fail to orchestrate immune responses to wound healing. Herein, vascular endothelial growth factor (VEGF) plasmids-loaded macrophage exosomes (Exos) were fabricated and enfolded in injectable self-healing hydrogels for programmed therapy of diabetic wounds through sequentially intrinsically modulating the inflammatory microenvironment and promoting angiogenesis. The hydrogels, formed via dynamical Schiff base reactions using modified polysaccharides, intrinsically regulate the inflammatory microenvironment via broad-spectrum antioxidant activity and macrophage phenotype regulation, restoring tissue redox and immune homeostasis. Furthermore, the hydrogels can stabilize and release the engineered exosomes. By integration of generation and release of VEGF by plasmids-loaded macrophage Exos, VEGF secretion by M2 macrophages, and enhanced binding of VEGF to VEGF receptor 2 by high affinity of sulfated chitosan, the intrinsic immunomodulatory hydrogels effectively promote the angiogenesis and accelerate the diabetic wound healing process.