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

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/AuPd_shells/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.