Piezoelectric Nanozymes With Acoustically Rejuvenated Catalytic Activities Rewire Lipid Metabolism for Two‐Pronged Ferroptotic Therapy

Spatiotemporal activation of nanozyme activity remains a major hurdle for minimizing off-target effects in nanocatalytic therapy. Concurrently, lipid metabolism-driven ferroptosis resistance impairs the efficacy of reactive oxygen species-based cancer treatments. Herein, we design an ultrathin, defective CuFe-based piezoelectric nanozyme (SPzyme) that integrates acoustically activated enzymocatalytic effects and lipid metabolic rewiring ability for the precise induction of ferroptotic induction. Notably, the generated oxygen/metal vacancies endow SPzyme nanosheets (∼3.6 nm thick) with enhanced piezoelectricity and distinctively quiescent basal enzymocatalytic activity compared to their defect-free counterparts. Upon ultrasound (US) stimulation, SPzymes exhibit markedly rejuvenated peroxidase- and glutathione peroxidase-like activities. Theoretical calculations demonstrate that planar defects and strain-induced polarization lower the energy barriers for catalytic ROS production via phonon-electron coupling effects. Furthermore, after the loading of a phospholipase inhibitor, the obtained SPzyme-D effectively remodels cellular lipid metabolism by enriching polyunsaturated phospholipids and inhibiting phospholipid detoxification, thereby sensitizing hepatocellular carcinoma cells to ferroptosis. In vivo evaluations corroborate that SPzyme-D upon US irradiation achieves 86.2% tumor inhibition with negligible systemic toxicity. Our study establishes a paradigm for designing biocompatible piezoelectric nanozymes with spatiotemporally controlled piezocatalytic/enzymocatalytic activities for precise and two-pronged ferroptotic therapy.