Smart multifunctional ROS-responsive supramolecular hydrogel for simultaneously regulating oxidative stress, immune dysregulation, and bacterial infection in diabetic wound healing

Diabetic wounds present a significant clinical challenge due to prolonged inflammation and impaired healing associated with excessive reactive oxygen species (ROS) and macrophage dysfunction. In this study, we developed a smart multifunctional ROS-responsive supramolecular hydrogel composed of carboxymethyl chitosan (CMCS) that is dynamically crosslinked by inclusion complexes of β-cyclodextrin (βCD) and ferrocene (Fc). This hydrogel facilitates the on-demand release of interleukin-4 (IL-4) while exhibiting intrinsic antibacterial properties. The IL-4-loaded hydrogel (IL-4@Gel-CD/Fc) responds to elevated H 2 O 2 levels, destabilizing βCD/Fc crosslinking through the Fenton reaction, which simultaneously promotes ROS scavenging and accelerates IL-4 release. The system subsequently reprograms macrophages from the proinflammatory M1 phenotype to the anti‒inflammatory M2 phenotype, thereby addressing immune dysregulation in diabetic wounds. In vitro evaluations demonstrated significant reductions in ROS levels, effective M2 macrophage polarization, and antibacterial activity. In vivo studies using a diabetic rat model revealed that, compared to controls, IL-4@Gel-CD/Fc significantly enhanced wound closure, collagen density, and angiogenesis while reducing proinflammatory cytokines (IL-6 and TNF-α) and increasing anti‒inflammatory cytokine IL-10 levels. Overall, this smart hydrogel system offers a novel strategy to simultaneously regulate oxidative stress, immune dysregulation, and bacterial infection, thereby promoting effective wound healing in diabetic conditions.