Glucose/ROS dual-responsive mitochondria-targeting nanozyme microneedles remodel mitochondrial homeostasis to orchestrate immune metabolic reprogramming for diabetic foot ulcer healing

Diabetic foot ulcers (DFUs) develop a persistent vicious loop featuring impaired mitochondrial activity and massive buildup of reactive oxygen species (ROS), accompanied by disordered immune responses; these combined pathological changes hinder the regeneration of damaged tissues. Therapeutic strategies that spatiotemporally target mitochondria to couple redox homeostasis restoration, immunometabolic reprogramming and tissue regeneration remain an unmet clinical need. Here we report a glucose/ROS dual-responsive microneedle patch incorporating mitochondria-targeting metal-phenolic nanozymes for DFU treatment. Tannic acid-cerium (TA-Ce) nano-catalysts possess strong catalytic capacities analogous to natural superoxide dismutase and catalase enzymes. These dual biomimetic functions clear excess ROS, stabilize mitochondrial physiological balance and drive macrophages to shift from pro-inflammatory M1-type toward anti-inflammatory M2 subtypes, which ultimately breaks sustained inflammatory feedback loops. Notably, the nanozyme functions dually as a therapeutic agent and a dynamic crosslinker through reversible boronate ester chemistry, allowing stable loading and microenvironment-responsive, on-demand release aligned with the pathological features of diabetic wounds. In a full-thickness diabetic rat wound model, the microneedle patch achieves 92.64% wound closure on Day 14, significantly outperforming commercial dressings. This work establishes a mitochondria-centered immunometabolic therapeutic strategy and provides a translatable platform for chronic wound regeneration.