Piezoelectric Catalysis Induces Tumor Cell Senescence to Boost Chemo‐Immunotherapy

Cellular senescence, a vulnerable state of growth arrest, has been regarded as a potential strategy to weaken the resistance of tumor cells, leading to dramatic improvements in treatment efficacy. However, a selective and efficient strategy for inducing local tumor cellular senescence has not yet been reported. Herein, piezoelectric catalysis is utilized to reduce intracellular NAD+ to NADH for local tumor cell senescence for the first time. In detail, a biocompatible nanomedicine (BTO/Rh‐D@M) is constructed by wrapping the piezoelectric BaTiO3/(Cp*RhCl2)2 (BTO/Rh) and doxorubicin (DOX) in the homologous cytomembrane with tumor target. After tumors are stimulated by ultrasound, negative and positive charges are generated on the BTO/Rh by piezoelectric catalysis, which reduce the intracellular NAD+ to NADH for cellular senescence and oxidize H2O to reactive oxygen species (ROS) for mitochondrial damage. Thus, the therapeutic efficacy of tumor immunogenic cell death‐induced chemo‐immunotherapy is boosted by combining cellular senescence, DOX, and ROS. The results indicate that 23.9% of the piezoelectric catalysis‐treated tumor cells senesced, and solid tumors in mice disappeared completely after therapy. Collectively, this study highlights a novel strategy to realize cellular senescence utilizing piezoelectric catalysis and the significance of inducing tumor cellular senescence to improve therapeutic efficacy. Piezoelectric nanoparticles BaTiO3/(Cp*RhCl2)2 (BTO/Rh) and doxorubicin (DOX) are encapsulated in tumor cell membranes to form nanomedicine (BTO/Rh‐D@M). Ultrasound induces a charge on BTO/Rh, reducing NAD+ to NADH for cellular senescence and tumor immunity, while oxidizing H2O to ROS. Combined with DOX, it effectively eliminates weakened senescent cells, greatly enhancing treatment efficacy.