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The anticancer mechanism of nanozymes is dominantly associated with the capacity for generation of reactive oxygen species (ROS) caused by the valence change of metal elements. However, very little research is focused on and has achieved the exploration and development of enzyme‐mimicking activities of valence‐invariable metal compounds. Herein, a distinct valence‐invariable calcium fluoride (CaF2) nanozyme with ultrasound (US)‐enhanced peroxidase (POD)‐mimicking activity is rationally designed and engineered for efficient calcium (Ca2+)‐overload‐enhanced catalytic tumor nanotherapy, which is the first paradigm of Ca‐based nanozymes for catalytic cancer treatment. The release of exogenous Ca2+ ions from CaF2 nanocrystals and deleterious ROS generation derived from US‐amplified POD‐mimicking properties facilitate intracellular Ca2+ accumulation and achieve Ca2+‐overload‐induced mitochondrial dysfunction through introducing exogenous Ca2+ ions and regulating calcium‐pumping channels of neoplastic cells. Especially, US as an exogenous energy input is capable of substantially amplifying POD‐mimicking catalytic activities of CaF2 nanozyme, ultimately achieving efficient anti‐neoplastic outcome on both 4T1 breast tumor and H22 hepatic carcinoma animal models. Such a discovery of enzyme‐like activity of valence‐invariable metal compounds can broaden the cognition scope of nanozymes and effectively serves the field of catalytic and chemoreactive nanomedicine.

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