A ROS-Responsive Injectable Hydrogel Platform Reprograms the Diabetic Wound Microenvironment to Enable Exosome Therapy

Diabetic wounds persist because excessive reactive oxygen species (ROS) sustain chronic inflammation and disrupt the regenerative microenvironment, impairing the stability and function of bioactive therapeutic components, including stem cells and extracellular vesicles (EVs). Here, an injectable hyaluronic acid (HA) hydrogel integrates microenvironment modulation with regenerative cue delivery by co-encapsulating ROS-responsive cerium oxide nanozymes (CeO₂ NPs) and mesenchymal stem cell-derived exosomes (EXOs). In this system, CeO₂ NPs act as antioxidant regulators that respond to oxidative stress, while EXOs provide regenerative signals for tissue repair. CeO₂ NPs are packaged within a thioketal-linked PLGA-PEG shell, enabling ROS-triggered degradation and on-demand activation, whereas the in situ crosslinked HA network serves as a localized matrix that protects components and synchronizes their sustained co-release. Under high-glucose conditions, the composite hydrogel reduces intracellular ROS, restores mitochondrial membrane potential, and enhances proliferation, migration, and angiogenic activity of endothelial cells and fibroblasts. In a diabetic mouse wound model, the hydrogel accelerates wound closure, accompanied by attenuated oxidative stress and inflammation, enhanced neovascularization and re-epithelialization, organized collagen remodeling, and a shift of macrophages toward a pro-regenerative M2 phenotype. This pathology-responsive antioxidant-regenerative coupling strategy establishes a rational, modular platform for overcoming microenvironmental constraints in exosome-based regenerative therapies.