Rational Design of a Multifunctional Copper‐Cobalt Sulfide Nanozyme for Cholesterol Depletion and Thermo‐Resistant Tumor Ablation

ABSTRACT Cholesterol accumulation in tumors contributes to therapeutic resistance and attenuates treatment efficacy. Here, we report a bimetallic sulfide nanozyme‐copper‐doped cobalt sulfide (CCS)‐derived from metal–organic framework (MOF) precursors, for synergistic tumor therapy. Copper doping narrows the bandgap, facilitates electron transfer, and lowers the activation barrier of cobalt sulfide, thereby enhancing photothermal and catalytic performance, as validated by experimental and computational analyses. Surface PEGylation and co‐loading with cholesterol oxidase (ChOx) and a thermolabile radical initiator (AIPH) yields a multifunctional nanoplatform termed CCSCA. This construct simultaneously depletes tumoral cholesterol and glutathione, elevating reactive oxygen species (ROS) levels. Upon 808 nm laser irradiation, CCSCA generates hyperthermia and pyrolyzes AIPH to produce alkyl radicals, enabling combined photothermal and thermodynamic therapy. Released copper and cobalt ions further enhance ChOx activity, catalyzing cholesterol oxidation to cholestenone and H 2 O 2 . Cholesterol reduction and cobalt ions from CCSCA downregulate heat shock proteins, sensitizing tumors to hyperthermia. This multi‐pronged strategy synergistically induces ferroptosis and apoptosis, resulting in potent antitumor efficacy in murine models with minimal systemic toxicity. Our findings highlight a rational design for multifunctional nanozymes and underscore cholesterol modulation as a viable strategy for overcoming tumor resistance.