Self‐Cascade of ROS/Glucose‐Scavenging Immunomodulatory Hydrogels for Programmed Therapeutics of Infected Diabetic Ulcers via Nrf2/NF‐κB Pathway

Abstract Diabetic ulcers (DUs) are characterized by a microenvironment with high oxidative stress, high blood glucose levels, and recalcitrant bacterial infections. This microenvironment is accompanied by long‐term suppression of endogenous antioxidant systems, which makes their clinical management extremely challenging. To address this issue, a hybridized novel gold‐palladium (AuPd) nanoshell of the injectable/injectable hydrogel system UiO/AuPdshells/BNN6/PEG@Gel (UAPsBP@Gel) is developed. The system is capable of acting as a nitric oxide (NO) reactor utilizing synergistic therapy that harnesses NIR‐II light‐triggered photothermal effects and controlled release of NO gas for synergistic treatment to eradicate biofilm infections at different depths. The AuPd nanoshells exhibits superoxide dismutase (SOD)‐, glucose oxidase (GOx)‐, and catalase (CAT)‐like activities, enabling self‐cascade process for scavenging both reactive oxygen species (ROS) and glucose. This activity reshapes the DUs microenvironment, switches on the endogenous antioxidant Nrf2/HO‐1 pathway and inhibits the NF‐κB pathway, promotes macrophage polarization toward the anti‐inflammatory M2 phenotype, and reduces oxidative stress, resulting in efficient immunomodulation. In vitro/in vivo results demonstrate that the UAPsBP@Gel can multifacetedly enhance the epithelial rejuvenation process through wound hemostasis, pro‐cellular migration and vascularization. These results highlight that a programmed therapeutic based on UBAPsP@Gel tailored to the different stages of infected DUs can meet complex clinical needs.