Glucose-responsive cascade nanozyme for controlled ROS release and bacterial carbon metabolic reprogramming in...

Chronic bacterial infections in diabetic wounds remain a major clinical challenge due to persistent inflammation, biofilm formation, and antibiotic resistance. Herein, we report a glucose-responsive cascade nanozyme system (PPCG) that functions as a microenvironment-adaptive reactive oxygen species (ROS) delivery platform for localized treatment of infected diabetic wounds. The PPCG integrates glucose oxidase (GOx) with a PdPtCu nanozyme core, enabling a triggered and self-sustaining catalytic cycle that amplifies ROS generation in glucose-rich infectious microenvironments while minimizing ROS release in glucose-deficient healthy tissue. GOx initiates the cascade by converting glucose into gluconic acid and H₂O₂. This locally generated H₂O₂ is then transformed into hydroxyl radicals via peroxidase- and glutathione oxidase-like activities, while catalase-like activity decomposes excess H₂O₂ into oxygen to reinforce the catalytic loop. Upon near-infrared-II laser irradiation, PPCG further enables synergistic photothermal disruption of bacterial biofilms. Multi-omics analyses revealed that PPCG triggers severe redox imbalance and metabolic stress, including impairing glucose uptake and glycolytic flux, triggering maladaptive carbon metabolic reprogramming, and ultimately resulting in ATP depletion and bacterial collapse. This spatiotemporally controlled ROS-generating platform represents a promising infection therapy that couples nanozyme cascade catalysis with metabolic targeting for enhanced bacterial eradication and minimal off-target effects.