Multi‐Scale Rational Design and Synergistic Strategies of Nanozymes for Targeting Drug‐Resistant Pathogens

ABSTRACT The escalating issue of drug‐resistant pathogens, largely driven by the overuse of conventional antibiotics, has become a significant global health threat. Developing alternative therapeutic strategies and fabricating natural biological enzyme materials that mimic the high efficiency, selectivity, and mild‐operating conditions of natural enzymes is a promising approach but presents a significant challenge. Nanozymes—nanomaterials exhibiting enzyme‐like catalytic activities—have emerged as innovative therapeutic platforms combining intrinsic antimicrobial properties with enhanced drug delivery capabilities. This review systematically elaborates on the concept, evolution, classification, and design synthesis strategy of antibacterial nanozymes, ranging from the nanoscale to the atomic scale, with a focus on their morphology, structure, catalytic activity, antimicrobial properties, stability, and reusability. It examines the antimicrobial mechanisms of nanozymes across three primary pathways: oxidative stress induction, metal ion release, and nonoxidative interactions, and further explores the synergistic outcomes enabled by their multimodal integration. It also evaluates the enhanced antibacterial effects achieved by nanozyme–antibiotic composites (NACs)—engineered hybrid systems that combine nanozymes with traditional antibiotics. Key synergistic mechanisms include increased reactive oxygen species (ROS) production alongside glutathione (GSH) depletion, enhanced antibiotic retention for controlled release, and membrane disruption to facilitate drug entry, resulting in a more potent “1 + 1 > 2” effect. Clinical applications of antibacterial nanozymes and NACs are also discussed, focusing on their potential to combat drug‐resistant infections. Ultimately, the review identifies current research gaps and proposes future directions, highlighting the crucial role of these nanozyme‐based therapies in advancing global efforts against drug‐resistant infections.