Atomic‐Precision Triple‐Enzyme Nanozyme Synchronizes Mitochondrial Dual‐Pathway Disruption for Precision Oncology

Abstract Although nanozyme‐mediated disruption of mitochondrial homeostasis holds significant therapeutic potential, precise spatiotemporal regulation using single‐function catalysts remains a major challenge. To overcome this limitation, we developed a triphenylphosphine‐functionalized Pd@PtIr nanozyme by epitaxially depositing a Pt–Ir (1:1) alloy shell onto Pd nanocube cores with atomic‐level precision. This rationally engineered metal‐center architecture generates a synergistic catalytic interface that not only enhances peroxidase‐like activity—validated by density functional theory (DFT)—but also endows the nanozyme with intrinsic NADH oxidase and glutathione peroxidase‐like functionalities within a single platform. Upon 808 nm near‐infrared (NIR) irradiation, the nanozyme triggers a cascade of enzyme‐mimetic redox reactions that jointly deplete mitochondrial glutathione (GSH) and elevate reactive oxygen species (ROS) levels, while NADH oxidation concurrently disrupts ATP biosynthesis. These concerted effects synergistically impair mitochondrial redox homeostasis and energy metabolism in tumor cells. To further potentiate therapeutic efficacy, we combined the nanozyme with antisense oligonucleotide‐mediated silencing of ASncmtRNA, resulting in a pronounced 89.1% tumor regression in an orthotopic breast cancer model. This integrated approach—combining atomic‐precision catalyst design, multifunctional enzymatic activity, and gene‐silencing therapy—presents a transformative paradigm for organelle‐targeted precision nanotherapeutics in oncology.