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

ABSTRACT 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.