Exosomes laden self-healing injectable hydrogel enhances diabetic wound healing via regulating macrophage polarization to accelerate angiogenesis

Developing multifunctional wound dressings capable of inducing rapid angiogenesis provides promise for diabetic wound healing, and triggering proper immune responses has been proposed as a potential way to facilitate angiogenesis. Here, we developed exosomes-laden injectable hydrogel with self-healing ability based on chitosan-graft-aniline tetramer (CS-AT) and dibenzaldehyde-terminated poly (ethylene glycol) (PEG-DA), which can enhance diabetic wound healing by stably releasing exosomes. In vivo, CS-AT hydrogel loaded with exosomes (CS-AT-Exo hydrogel) apparently accelerated the diabetic full-thickness wound healing, characterized by promoted wound healing efficiency, quick re-epithelization, favorable collagen deposition, and abundant angiogenesis at the wound beds. In addition, the synergistic effect of hydrogel and exosomes induced local regulation of M2 macrophages polarization. In vitro, CS-AT hydrogel and exosomes can synergistically promote the polarization of M2 macrophages in CS-AT-Exo hydrogel. Furthermore, the CS-AT-Exo hydrogel with coculture of macrophages significantly enhanced the ability of human umbilical vein endothelial cells (HUVECs) to proliferation, migration, and tube formation. These findings revealed important mechanisms by which multifunctional CS-AT-Exo hydrogels with continuous exosomes release can enhance angiogenesis and diabetic wound healing by synergistically inducing M2 macrophage polarization, suggesting a potential treatment strategy for diabetic wounds.