Click-crosslinked nano-hydrogel enables metabolic immune reprogramming for diabetic foot ulcers.

Diabetic foot ulcers (DFUs) pose significant therapeutic challenges owing to their intricate microenvironment. Conventional biomaterials often target only a single pathological factor, rendering them inadequate for halting the progressive deterioration of DFUs. To address this limitation, we developed a multifunctional drug delivery platform based on amine-yne click chemistry. The system was constructed using quaternized chitosan (QCS) and tetra-arm polyethylene glycol propiolate (4A-PEG-PA), incorporating metal-polyphenol nanoparticles (MPNs) formed by epigallocatechin gallate (EGCG) and magnesium ions (Mg2+) as the drug-loading component. This platform not only fills ulcer cavities to eliminate dead space but also adheres firmly to irregular wound surfaces, minimizing physical disruption. Additionally, the drug delivery system exhibits pH-responsive behavior, along with potent antioxidant and hypoglycemic effects, effectively lowering reactive oxygen species (ROS) and glucose levels in the wound microenvironment by modulating pH, thereby promoting healing. In vitro studies revealed that the material safeguards mitochondrial function and integrity by counteracting oxidative stress. In vivo evaluations further demonstrated its antimicrobial, anti-inflammatory, pro-angiogenic, and re-epithelialization properties. Collectively, this hydrogel-based platform integrates multiple bioactive functions, presenting a promising strategy for the clinical management of DFUs.