MnO2-passivated Co3O4 sonozymes for tumor microenvironment re-activated sonodynamic and chemodynamic enhanced immunotherapy.

Ultrasound-activated sonodynamic therapy (SDT) is showing more potential in the treatment of deep-seated tumors such as renal cell carcinoma because of the high tissue-penetration depth. However, existing sonosensitizers lack active-targeting ability and often have "always on" characteristics, leading to potential accumulation in normal tissues and causing damage under US irradiation. Herein, we present for the first time the "sonodynamic passivation strategy" for sonosensitizers to prevent ROS-induced damage to normal cells. MnO2 nanoflowers with TME-responsive degradation features are utilized to load on the surface of Co3O4 sonozymes, realizing the passivation of sonodynamic and chemodynamic activities of Co3O4. In addition to the passivated sonozyme catalytic activity, MnO2@Co3O4 heterojunctions are capable of regulating the immunosuppressive tumor microenvironment (TME) by depleting GSH and alleviating hypoxia. Owing to the TME-responsive degradation of MnO2, the tumor-specific released Co3O4 sonozymes can restore their sonodynamic and chemodynamic activities, achieving the in-situ SDT/CDT and then realizing the trigger of ICD. Meanwhile, the released Mn ions can not only realize the cascade amplification of ROS production through Fenton-like reaction, GSH depletion, and hypoxia alleviation, but also activate cGAS-STING pathway for the augmentation of antitumor immune response. The activation of cGAS-STING pathway is further enhanced by the loading of STING agonist MSA-2 on the surface of Co3O4 before the coating of MnO2. MnO2@Co3O4/MSA-2-mediated TME-reactivated SDT/CDT/cGAS-STING-activation has shown significant antitumor efficacy, resulting in the eradication of primary tumors and the inhibition of distant tumor growth. Overall, this work offers hopeful insights into the modulation of the "on/off" function of sonosensitizer activity, ultimately enabling precise sonodynamic therapy for refractory renal cell carcinoma.