摘要
Insufficient generation of reactive oxygen species and the highly active cholesterol metabolism of tumors are two major barriers limiting the efficacy of conventional ferroptosis-based cancer therapies. Here, we engineered a single-atom iron nanozyme (Fe-NC@TASIN-30@FA, abbreviated as FTF) to overcome ferroptosis resistance and sensitize tumors to apoptosis-coupled catalytic therapy by simultaneously delivering a distal cholesterol synthesis inhibitor and catalytically amplifying ROS production. FTF is constructed by loading a selective 7-dehydrocholesterol (7-DHC) synthesis inhibitor, TASIN-30, onto an iron single-atom nanozyme and further functionalizing it with folate-modified polyethylene glycol (SH-PEG-FA) to confer tumor-targeting capability. Notably, TASIN-30 is incorporated with a drug-loading rate of 22.5%, providing efficient payload delivery without compromising nanozyme activity. The iron active centers in FTF exhibit dual enzyme-mimetic activities. One of them is peroxidase-like activity that breaks down H 2 O 2 into hydroxyl radicals, and the other is glutathione peroxidase-like activity that catalyzes the oxidation of reduced glutathione to oxidized glutathione, thereby increasing intracellular ROS levels and consuming antioxidants to achieve a coordinated iron apoptosis effect. In addition, by inhibiting 7-DHC and cholesterol biosynthesis, FTF accelerates the consumption of excess intracellular cholesterol in tumor cells, disrupts the integrity of lipid rafts, and consequently suppresses tumor cell proliferation. In 143B tumor-bearing nude mice, FTF achieves an in vivo tumor inhibition rate of approximately 82.5%, while exhibiting a maximum tolerated dose of 7.5 mg/kg. Overall, this study proposes a new therapeutic strategy that integrates cholesterol metabolic interference with catalytic nanozyme therapy, providing a potent ferroptosis-apoptosis synergistic modality for tumors refractory to conventional treatments.
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