Generating Reactive Oxygen Species by a Dual-Catalytic Metal–organic Framework-based Nanozyme against Drug-resistant Bacteria Infection

Oxidase-like artificial enzymes (AEs) are rapidly developing for their attractive reactive oxygen species (ROS)-generating capacity in biological applications. However, efficient strategies to improve the AE catalytic performance by modulating the electron transfer (ET) process remain limited. Herein, a new electron transfer pathway in the de novo-designed MOF-based oxidase mimics (ZCA-X) is reported. The electron structure of the active center is regulated to form a unique Au–N–Cu domain for boosting ROS against drug-resistant bacteria. Unlike classical cascade catalytic systems depending on hydrogen peroxide or photocatalysts with complex regulation of band structure, the oxidase-like ZCA-20 catalyzes oxygen reduction via a direct four-ET process without simulation or a specific substrate. The Au–N–Cu active domain formed by charge transfer between Au NCs and CuN4 single site exhibits high catalytic efficiency (kcat = 3.61 s–1), generating ROS as intermediate products. ZCA-20 AE is employed in catalytic eradication against drug-resistant bacteria in ROS-mediated structural damage, showing remarkable therapeutic effects both in vitro and in vivo. This strategy of modulating the ET process by coupling different active sites might inspire the development of new AEs with high selectivity and enzymatic activity.