Environmentally Responsive Catalytic Microneedles Enable Cascade Fenton Reaction for Antibacterial Therapy and Accelerated Infected Wound Healing

ABSTRACT The persistence of bacterial biofilms and resistance limits the efficacy of traditional therapies, slowing tissue regeneration. Here, we report an innovative pH‐responsive catalytic microneedle system (GZIF@Fe MN) designed to combat bacterial infections by disrupting bacterial redox homeostasis through a cascade Fenton reaction, generating highly reactive hydroxyl radicals (·OH). The system utilizes a Schiff base reaction between oxidized hyaluronic acid and carboxymethyl chitosan to construct a pH‐sensitive microneedle matrix capable of transdermal and delivery of embedded glucose oxidase (GOx) and Fe 3+ ‐modified metal‐organic framework ZIF‐8 (ZIF@Fe) for deep tissue release. The catalytic product of GOx, gluconic acid, creates an acidic microenvironment that facilitates the degradation of ZIF@Fe, leading to the rapid release of Fe 3+ . Simultaneously, GOx catalyzes glucose metabolism to generate H 2 O 2 , which drives continuous production of ·OH, enhancing the bactericidal effect. In vitro studies demonstrate that the cascade reaction achieves nearly 99% bactericidal efficacy against S. aureus and E. coli . In vivo experiments reveal that GZIF@Fe MN promotes macrophage polarization toward the anti‐inflammatory M2 phenotype, thereby reducing excessive inflammation and facilitating tissue regeneration, with wound closure exceeding 90%. Overall, the GZIF@Fe MN system provides an effective antibacterial wound therapy strategy and offers new insights into the development of next‐generation antibacterial biomaterials.