Oxygen Vacancy‐Engineered CaCu ₃ Ti ₄ O ₁₂ Nanocatalyst for Piezoelectrically Driven Cascade Apoptosis/Cuproptosis/Ferroptosis Therapy

ABSTRACT Ultrasound (US) induced piezoelectric catalytic therapy is an emerging cancer treatment method. However, the development and optimization of piezoelectric catalyst remain the major challenge. Herein, we have converted the classical dielectric material CaCu 3 Ti 4 O 12 (CCTO) into an efficient piezoelectric material through oxygen vacancy (V O ) engineering, enabling piezoelectric catalytic‐driven cascade tumor therapy. The introduction of V O results in strong polarization and a robust piezoelectric coefficient. Density functional theory (DFT) calculations reveal that V O acts as an electron trap to suppress the recombination of electron and hole, enhancing the catalytic efficiency. The piezoelectric effect can “open” the cell membrane, facilitating the materials influx and triggering reactive oxygen species (ROS) storm. Meanwhile, the cavitation effect of US and tumor cell over‐expressed glutathione (GSH) accelerate Cu and Ca release, causing intracellular ions overload. ROS and Ca ions damage mitochondria to evoke apoptosis, which accordingly shuts down the Cu + outflow pathway and expedites cuproptosis. Moreover, ROS and GSH depletion triggers ferroptosis. This process establishes a positive feedback loop mechanism. Transcriptome sequencing confirms the activation of cell death‐related pathways. This study represents the first paradigm to create piezoelectricity through V O in CCTO for tumor therapy, advancing the applications of quadruple perovskites in tumor treatment.