Transformable Tumor Microenvironment‐Responsive Oxygen Vacancy‐Rich MnO 2 @Hydroxyapatite Nanospheres for Highly Efficient Cancer Sonodynamic Immunotherapy

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.