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Despite the promise of sonodynamic processes in cancer therapy, existing sonosensitizers often fail to regulate the generation of reactive oxygen species (ROS) against tumors, potentially leading to off-target toxicity to normal tissues. We report a transformable core-shell nanosonosensitizer (TiO2 @CaP) that reinvigorates ROS generation and dissolves its CaP shell to release Ca2+ in an acidic tumor microenvironment (TME) under ultrasound activation. Thus, TiO2 @CaP acts as a smart nanosonosensitizer that specifically induces mitochondr