Pt(IV) prodrug as a potent nanosonosensitizer self-cyclically amplifies sonodynamic-chemotherapy with dually reversing cisplatin resistance.

Although sonodynamic therapy (SDT) has shown promising advancements in combination with chemotherapy, it frequently necessitates the requirement of conventional sonosensitizers and chemotherapeutic agents, engendering intricate systems and potential drug resistance. Herein, we fabricated a potent Pt(IV)-poly(amino acid) coordination nanosonosensitizer (PHPt) with dual reversal of cisplatin resistance, producing abundant ¹O₂ and ˙OH upon ultrasound irradiation without the use of any external sonosensitizers. The Pt(IV) prodrug in PHPt efficiently reduced to cisplatin through SDT-induced ˙H and glutathione (GSH), inducing ˙OH accumulation and CDDP release, which further amplified the oxidative stress on SDT. Moreover, the high GSH depletion performance of PHPt and administration of aspirin effectively inhibited cisplatin detoxification and activation of the nuclear factor-kappa B pathway, respectively. This cooperative action between the Pt(IV) prodrug and SDT in the tumor microenvironment promoted self-cyclic amplification of sonodynamic-chemotherapy, achieving a significant tumor inhibition rate of 99.4%. Thus, this study offers novel perspectives on the sonosensitizer development and cisplatin application in SDT.