A Smart MMP‐9‐responsive Hydrogel Releasing M2 Macrophage‐derived Exosomes for Diabetic Wound Healing

This work presents a smart MMP-9-responsive hydrogel fabricated through cross-linking of oxidized dextran, MMP-9-sensitive peptides, and carboxymethyl chitosan loaded with M2-Exos. The hydrogel performs diagnostic logic and accordingly determines M2-Exo release kinetics when the MMP-9 increases in an inflammatory microenvironment. M2-Exos released on demand promotes the polarization of macrophages, initiating the inflammatory-proliferative phase transition to promote diabetic wound healing.

Abstract

Chronic diabetic wounds are characterized by prolonged inflammation and excessive accumulation of M1 macrophages, which impede the healing process. Therefore, resolving inflammation promptly and transitioning to the proliferative phase are critical steps for effective diabetic wound healing. Exosomes have emerged as a promising therapeutic strategy. In this study, a smart hydrogel capable of responding to pathological cues in the inflammatory microenvironment to promote the transition from inflammation to proliferation by delivering M2 macrophage-derived exosomes (M2-Exos) is developed. The smart hydrogel is synthesized through the cross–linking of oxidized dextran, a matrix metalloproteinase (MMP)-9-sensitive peptide, and carboxymethyl chitosan containing M2-Exos. In response to elevated MMP-9 concentrations in the inflammatory microenvironment, the hydrogel demonstrates diagnostic logic, adjusting the release kinetics of M2-Exos accordingly. The on-demand release of M2-Exos facilitated macrophage polarization from the M1 to the M2 phenotype, thereby promoting the transition from the inflammatory to the proliferative phase and accelerating diabetic wound healing. The transcriptomic analysis further reveals that the MMP-9-responsive hydrogel with M2-Exos delivery exerts anti-inflammatory and regenerative effects by downregulating inflammation-related pathways. This study introduces an innovative, microenvironment-responsive exosome delivery system that enables precise control of therapeutic agent release, offering a personalized approach for the treatment of chronic diabetic wounds.