Glucose-regulating hydrogel for immune modulation and angiogenesis through metabolic reprogramming and LARP7-SIRT1 pathway in infected diabetic wounds

Abstract

In diabetic-infected wounds, the local hyperglycemic state leads to unique pathological characteristics of diabetic ulcers, such as secondary chronic infections, abnormal angiogenesis, oxidative stress, and diabetic peripheral neuropathy. Glucose oxidase (GOx) is an enzyme that catalyzes the breakdown of glucose into hydrogen peroxide and gluconic acid, making it a candidate enzyme for regulating the hyperglycemic microenvironment in diabetic wounds. However, multifunctional hydrogel therapeutic systems built around the glucose-lowering capability of GOx have rarely been reported. Here, we loaded stachydrine and Au–FePS₃ nanosheets onto a quaternized chitosan (QC) - oxidized dextran (OD) hydrogel to construct a synergistic QC-OD@AF/S hydrogel therapeutic system. In vitro experiments showed that Au–FePS₃ possesses GOx-POD cascade catalytic activity, capable of reducing glucose concentration and decomposing generated hydrogen peroxide into reactive oxygen species (ROS). Concurrently, Au–FePS₃ exhibits excellent photothermal performance under 808 nm infrared light, synergistically exerting antibacterial capabilities with ROS and quaternary ammonium groups. Stachydrine has been demonstrated to mediate the metabolic reprogramming of macrophages and alleviate high-glucose-induced oxidative stress and impairment of angiogenesis in HUVECs through the LARP7-SIRT1 pathway. In summary, the QC-OD@AF/S hydrogel demonstrates superior capabilities in antibacterial activity, immune modulation, promotion of angiogenesis, and reduction of local glucose concentration, making it a potential clinical therapy.