Ultrasound‐Amplified Enzyodynamic Tumor Therapy by Perovskite Nanoenzyme‐Enabled Cell Pyroptosis and Cascade Catalysis

Overcoming apoptosis resistance to achieve efficient breast cancer treatment remains a challenge. The precise induction of another form of programmed cell death, pyroptosis, is an excellent alternative for treating cancer. Ultrasound (US)-enhanced enzyme dynamic (enzyodynamic) therapy is developed by employing LaFeO3 (LFO) perovskite nanocrystals as a substrate to increase the rate of deleterious reactive oxygen species (ROS) generation for intensive cell pyroptosis. LFO nanocrystals possess quadruple enzyme-mimicking activities, including oxidase-, peroxidase-, glutathione peroxidase-, and catalase-mimicking activities, which undertake the dominant therapeutic task through cascade catalytic reactions, including the reversal of hypoxic microenvironment, depletion of endogenous glutathione, and continuous output of ROS. US exogenous stimulation increases the transition rate of the intermediate complex to Fe (II) and favors incremental ROS production, by which the ROS burst-induced pyroptosis process is accomplished through the ROS-TXNIP-NLRP3-GSDMD pathway. Both in vitro and in vivo antineoplastic outcomes affirm the ascendancy of LFO nanozyme-induced pyroptosis. This work highlights the critical role of US coupled with nanocatalytic reactors in pyroptosis-dominant breast cancer treatment with the apoptosis resistance circumvention feature.