Stimulus-Responsive Nanozymes for Mitochondria-Targeted Therapy: Design, Mechanisms, and Biomedical Applications.

Mitochondrial dysfunction represents a common pathological hub in tumors, neurodegenerative diseases, cardiovascular diseases, and inflammatory degenerative diseases. Nanozymes offer new opportunities for precision intervention. However, inadequate targeting and uncontrollable activity remain major obstacles to their clinical translation. This review proposes a "trinity" synergistic design paradigm, which exploits pathological mitochondrial signals as dual-functional cues for both subcellular navigation and catalytic activation, thereby achieving temporal coupling of "targeting enrichment" and "responsive activation." Within this framework, we first summarize the three major categories of nanozyme material systems and their mitochondrial targeting strategies. Subsequently, we systematically analyze the structural design and activation mechanisms of endogenous, exogenous, and multi-stimulus synergistic responsive nanozymes. We also establish a cross-scale effect chain model that cascades from catalytic events to mitochondrial metabolic remodeling, programmed cell death, and immune regulation. On this basis, we comprehensively review the therapeutic applications of these nanozymes in oncology, neurological disorders, cardiovascular diseases, and inflammatory degenerative diseases. Finally, we analyze the critical challenges confronting this field and provide perspectives on future directions, with the aim of offering theoretical references and research ideas for the development of mitochondria-targeted intelligent nanomedicines.