Spatiotemporal NO/O ₂ -releasing cascade nanozyme microneedles enhance diabetic infected wound healing by modulating the immune microenvironment

<b>Rationale:</b> Chronic diabetic wounds present significant therapeutic challenges due to biofilm resistance and dysregulated metabolism of glucose, reactive oxygen species (ROS), and nitric oxide (NO), which collectively exacerbate immunosuppression and impair tissue repair. <b>Methods:</b> This study developed a glucose-driven cascade nanozyme-loaded dissolvable microneedle system (PPLG@MN) that enables spatiotemporal regulation of the wound microenvironment through a closed-loop mechanism involving nutrient deprivation, gas modulation, and immune reprogramming. The system consists of porous Prussian blue nanozymes (PPB) loaded with glucose oxidase (GOx) and L-arginine (L-arg), which is precisely delivered into the tissue via microneedles. <b>Results:</b> PPLG@MN initiates a self-sustaining therapeutic cycle within the biofilm microenvironment, in which GOx catalyzes the oxidation of glucose to generate hydrogen peroxide (H₂O₂), inducing bacterial starvation. Subsequently, H₂O₂ reacts with PPB and L-arg to release oxygen (O₂) and biofilm-disrupting NO, thereby alleviating local hypoxia and enhancing antibacterial efficacy. Furthermore, the synergistic action of O₂ and NO reprograms macrophages toward an anti-inflammatory M2 phenotype (approximately 30-fold increase compared to the model group), effectively resolving inflammation and promoting angiogenesis. <i>In vivo</i> studies confirmed that the system achieved > 99.9% biofilm eradication efficiency and accelerated wound healing by 25.6% compared to the model group. <b>Conclusion:</b> This nanoplatform offers a clinically translatable therapeutic strategy for biofilm-associated diabetic wounds by synergistically combining gas therapy and immune reprogramming.