Atomic‐Precision Triple‐Enzyme Nanozyme Synchronizes Mitochondrial Dual‐Pathway Disruption for Precision Oncology
Abstract
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.
Article Details
Authors (13)
Yufan Zhang
Key Laboratory of Photochemistry, Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences
Shuangshuang Yang
Qin Xiang
Marshall Laboratory of Biomedical Engineering, Precision Medicine and Health Research Institute, Shenzhen Key Laboratory for Nano-Biosensing Technology, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School
Jinkun Huang
Marshall Laboratory of Biomedical Engineering, Precision Medicine and Health Research Institute, Shenzhen Key Laboratory for Nano-Biosensing Technology, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School
Yongfeng Tan
Marshall Laboratory of Biomedical Engineering, Research Center for Biosensor and Nanotheranostic, School of Biomedical Engineering, Health Science Center Shenzhen University Guangdong 518060 P.R. China
Xiang Peng
Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology
Youming Feng
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering Nanjing University Nanjing 210023 P.R. China
Ran Chang
Jinze Li
CAS Key Lab of Bio-Medical Diagnostics
Yaru Cheng
Marshall Laboratory of Biomedical Engineering, Research Center for Biosensor and Nanotheranostic, School of Biomedical Engineering, Health Science Center Shenzhen University Guangdong 518060 P.R. China
Xuan Wang
Zhuangqiang Gao
Marshall Laboratory of Biomedical Engineering, Precision Medicine and Health Research Institute, Shenzhen Key Laboratory for Nano-Biosensing Technology, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School
Haifeng Dong
Marshall Laboratory of Biomedical Engineering, Precision Medicine and Health Research Institute, Shenzhen Key Laboratory for Nano-Biosensing Technology, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School