Advances in the Research of Dual-Atom Nanozymes for Tumor Therapy

Dual-atom nanozymes (DAzymes) provide a new research strategy for regulating catalytic reaction pathways and redox homeostasis in tumor microenvironments (TMEs) by constructing adjacent metal active centers with specific coordination environments. Compared to traditional nanoparticle nanozymes and single-atom nanozymes (SAzymes), DAzymes have shown potential advantages in electronic structure regulation, multi-substrate activation, and multi-step catalysis. However, there is still a lack of systematic understanding of the structure–activity relationship between their catalytic performance and therapeutic effects. This review focuses on the research progress of DAzymes in tumor therapy. Firstly, its structural definition and classification boundaries are clarified, and the construction strategy, structural characterization, and dynamic evolution of diatomic active sites during the reaction process are systematically summarized. Subsequently, the focus of this study is on elucidating the effects of bimetallic electronic coupling, spatial coordination, defect regulation, and reaction selectivity on the generation and clearance of reactive oxygen species (ROS), and analyzing the applicability of catalytic performance under physiological substrate concentrations and in a complex TME. On this basis, the application of DAzymes in chemodynamic therapy (CDT), multimodal combination therapy, and tumor-targeted delivery is summarized, and the relationship between catalytic reactions and ferroptosis, cuproptosis, immunogenic cell death (ICD), and tumor metabolic response is further explored. In response to the insufficient evidence of diatomic structures, unclear attribution of catalytic synergy, and limited in vivo effectiveness evaluation in existing research, the focus is on analyzing the evidence correlation between structural authenticity, catalytic mechanisms, and biological effects, and discussing transformation challenges such as active site stability, metal release, catalytic persistence, and long-term biosafety. Finally, it is proposed to establish a verifiable, comparable, and transformative DAzyme research system through standardized structural characterization, physiologically relevant catalytic evaluation, mechanism causality verification, and interpretable data-driven design. This review aims to provide a theoretical reference for revealing the structure catalytic therapeutic effect relationship of diatomic sites and developing precise tumor catalytic therapy strategies.