A NIR-II emissive sonosensitized biotuner for pyroptosis-enhanced sonodynamic therapy of hypoxic tumors

Pyroptosis is considered as a new way to effectively boost the immune response of tumors and inhibit tumor growth. Effective strategies to induce pyroptosis mainly rely on chemotherapeutic drugs and phototherapy, but their potential biotoxicity and phototoxicity limit their application in biomedicine. Herein, we designed a NIR-II emitting pyroptosis biotuner, Rd-TTPA, which induced pyroptosis under ultrasound irradiation to achieve pyroptosis-enhanced sonodynamic therapy (SDT) and immunogenic cell death (ICD) for tumors. Benefiting from its A-π-D₁-D₂ structure enhanced donor-acceptor interaction, Rd-TTPA can induce cell pyroptosis under both normoxia (21 % O₂) and hypoxia (2 % O₂) conditions by rapidly generating superoxide radicals (O₂^-•) upon ultrasound irradiation. The sonodynamic biotuner of pyroptosis overcomes the longstanding weakness of chemical drug and photosensitizer-based pyroptosis, such as drug resistance and limited penetration depth. In-depth studies demonstrated that Rd-TTPA can selectively target tumor cell mitochondria and possess excellent in vivo NIR-II fluorescence imaging capabilities. Administrating a tumor-bearing mouse model with Rd-TPPA, satisfying antitumor efficacy via pyroptosis-augmented SDT was achieved upon the guidance of NIR-II fluorescence imaging.