Piezoelectric electroporation potentiates high-frequency irreversible electroporation for enhanced prostate cancer eradication

Residual tumor cell persistence remains a critical unresolved barrier limiting focal therapy such as high-frequency irreversible electroporation (H-FIRE) for prostate cancer. In this study, we identified DNA damage repair as the central mechanism governing the reversible survival of residual cells after H-FIRE. By exploiting the transient membrane permeability of these residual cells following H-FIRE, we engineered a piezoelectrically active nanomaterial, BOIS. Exogenous electric pulses generated by H-FIRE enhance tumor membrane permeabilization, thereby facilitating the intracellular delivery of BOIS and promoting its efficient penetration into residual malignant cells. Upon ultrasound activation, BOIS induces surface charge separation and electron migration, producing an intrinsic electric field accompanied by reactive oxygen species (ROS). This dual mechanism cascade simultaneously inflicts endogenous electric field-mediated electroporation damage on both cellular and nuclear membranes and imposes lethal oxidative stress, thereby converting reversibly injured residual cells into an irreversible death trajectory. Consequently, residual tumor cells with damage repair capacity are converted from a reversibly injured state to irreversible lethal damage. Unlike conventional combination therapies, this study pioneered a new therapeutic paradigm in which the focal ablation procedure functions as a nanomaterial delivery mechanism, thereby establishing a self-reinforcing therapeutic loop. This strategy markedly amplified the therapeutic efficacy of H-FIRE and enhanced the eradication of residual tumor cells. Collectively, these findings establish a groundbreaking therapeutic paradigm for eliminating residual disease following focal ablation.