Acoustic-To-Electronic Transduction: Ultrasound-Triggered Reductive Elimination of Platinum(IV) Prodrugs for Deep-Tissue Metallodrug Activation

Abstract Platinum(IV) prodrugs offer an elegant paradigm for controlled chemotherapy, yet their clinical translation to deep-seated malignancies is fundamentally bottlenecked by the poor tissue penetration of optical triggers. Herein, we report an ultrasound-activatable platinum(IV) prodrug platform (TSZQ-OXA) that exploits sonocatalytic, electron-transfer-mediated reduction to achieve precise metallodrug activation in deep tumors. By designing and screening a donor−π–acceptor (D−π–A) small-molecule library based on a triphenylamine core, we identified TSZQ as a molecular mediator exhibiting ultrasound-responsive excited-state behavior and enhanced sonocatalytic redox activity. Covalent conjugation of TSZQ to a low-spin octahedral (d6) oxaliplatin-derived Pt(IV) scaffold afforded TSZQ-OXA. The integrated prodrug exhibits excellent biomimetic stability under physiological conditions but undergoes an acoustic-to-electronic cascade upon medical ultrasound irradiation. In the presence of biological reductants, ultrasound exposure drives concurrent sonodynamic singlet oxygen generation and reductive metal elimination to liberate active, DNA-reactive oxaliplatin (d8). This dual sonodynamic–chemotherapeutic mechanism triggers robust intracellular disruption inducing mitochondrial depolarization, concurrent apoptosis and lipid-peroxide-driven ferroptosis, and immunogenic cell death. Notably, TSZQ-OXA maintains its sonocatalytic responsiveness through severe deep-tissue barriers, translating into profound antitumor efficacy across subcutaneous, multi-drug-resistant, and deep orthotopic liver tumor models with excellent systemic tolerability. This work establishes a mechanistic framework for harnessing acoustic energy to drive controlled electronic transitions and metallodrug activation within deep-tissue regimes.