Lattice‐distortion Induced Niobium‐based Perovskite Polarization Cascade Regulates Na ⁺ /K ⁺ ATPase to Enhance Pyroptosis for Cancer Treatment

Abstract Designing lattice‐distortion‐induced perovskite materials to disrupt intracellular soNa ⁺ homeostasis via targeting sodium–potassium ATPase (Na ⁺ /K ⁺ ATPase) has emerged as a promising therapeutic strategy in cancer treatment. However, precise manipulation of Na ⁺ balance to achieve targeted anti‐tumor effects remains challenging. Here, a lattice‐distorted and oxygen vacancy‐rich niobium‐based perovskite, NaNbO ₃ (NNO _x ), is synthesized by utilizing the piezo‐catalytic and photothermal properties of NNO _x , and a cascade regulation of Na ⁺ /K ⁺ ATPase is achieved. Particularly, under ultrasound and near‐infrared II laser irradiation, NNO _x not only releases exogenous Na ⁺ to elevate local intracellular Na ⁺ concentrations but also efficiently generates reactive oxygen species, inducing mitochondrial damage and impairing ATP synthesis in tumor cells. This mitochondrial dysfunction dramatically reduces Na ⁺ /K ⁺ ATPase activity, impairs cellular Na ⁺ efflux, and further exacerbates intracellular Na ⁺ accumulation. Consequently, the severe ionic imbalance leads to rapid osmotic swelling and bubble formation, triggering pyroptotic cell death and robust anti‐tumor immune responses. In vitro and in vivo studies demonstrate that NNO _x efficiently suppresses tumor growth and activates potent anti‐tumor immunity, highlighting an innovative strategy for ionic disruption‐induced pyroptosis and immunogenic cell death. This approach provides valuable insights for future ionic homeostasis‐targeted cancer immunotherapy.