A Highly Potent Os@Au‐TPA Coordination Structure‐Based Sonosensitizer for Tumor Sono‐Immunotherapies

Abstract Ultrasound (US) becomes an appealing modality for stimulating or amplifying immune responses during cancer therapy, which is also termed sono‐immunotherapy. However, the clinical prospect has not been fully realized due to the scarcity of efficient sonosensitizers. Herein, for the first time a novel Os‐doped Au‐tri(pyridin‐4‐yl) amine coordination structure (Os@Au‐TPA)‐based sonosensitizer is originally designed and synthesized for sono‐immunotherapy of breast‐metastasized tumors. Impressively, Os@Au‐TPA shows much higher US‐mediated 1 O 2 ‐producing activity than Au‐TPA as well as the other traditional sonosensitizers, for example, ≈41.6 folds to ce6, 19.5 times to Protoporphyrin IX (PpIX), 12.0 to Indocyanine Green (ICG), and 11.1 to Iron phthalocyanine (Pc(Fe)). The Os@Au‐TPA can not only generate abundant ROS upon US irradiation to implement sonodynamic therapy (SDT), stimulating cell apoptosis and further immunogenic cell death, but can also generate O 2 to alleviate hypoxia to promote the polarization of M2 to M1 macrophages to enhance tumor immunogenicity. As a result, when combined with PD‐L1 antibody, it remodels the immunosuppressive tumor microenvironment, achieves concurrent sonodynamic‐triggered immune activation, and eradicates both the original and distant‐metastasized tumors efficiently. This work not only provides a new strategy to construct potent sonosensitizers from pyridine‐metal coordination structures but also proves that sonosensitizers with high performance are crucial in boosting cancer sono‐immunotherapy.