Abstract
Despite the promise of sonodynamic therapy (SDT)-mediated immunotherapy, the anticancer efficacy of current sonosensitizers is greatly limited by the immunosuppressive tumor microenvironment (TME) and their inability to selectively respond to it. Herein, oxygen vacancy-rich MnO(2)@hydroxyapatite (Ca(10)(PO(4))(6)(OH)(2)) core-shell nanospheres (denoted as O(v)-MO@CPO) as an advanced TME-responsive sonosensitizer for sonodynamic immunotherapy is demonstrated. The O(v)-MO@CPO maintains its structural integrity under neutral conditions but dissolves the pH-sensitive hydroxyapatite shell under acidic TME to release active oxygen vacancy-rich MnO(2) core, which reinvigorates H(2)O(2) consumption and hypoxia alleviation due to its catalase-like activity. Furthermore, the introduced oxygen vacancies optimize the electronic structure of O(v)-MO@CPO, with active electronic states near the Fermi level and higher d-band center. It results in accelerated electron-hole pair separation and lower catalytic energy barriers to boost ultrasound (US)-initiated ROS production. These multimodal synergistic effects effectively reverse the immunosuppressive tumor microenvironment, inhibiting tumor growth and metastasis in 4T1 tumor-bearing mice. No evident toxic effects are observed in normal mouse tissues. Additionally, when combined with an immune checkpoint inhibitor, O(v)-MO@CPO-mediated SDT further improves the effectiveness of immunotherapy. This work affords a new avenue for developing TME-dependent sonosensitizers for SDT-mediated immunotherapy.