Membrane-anchoring clickable Iridium(III) nanosonosensitizer in situ evokes PANoptosis for augmented tumor sono-immunotherapy

Developing activatable "off-on" sonosensitizers with superior sonodynamic activity and immunogenic cell death (ICD) induction ability is urgently needed for precise and boosted tumor sono-immunotherapy. Herein, a membrane-anchoring clickable Iridium(III) nanosonosensitizer is well-designed to elicit tumor-specific PANoptosis for enhanced sonodynamic therapy (SDT) and amplified immune activation. A click-activatable tetrazine-functionalized Iridium(III) sonosensitizer Tz-Ir with dual type I/II reactive oxygen species (ROS) generation ability is developed, and further encapsulated into crosslinked human serum albumin (HSA) to form acid-responsive nanosonosensitizer HSA@Tz-Ir. After tumor-targeting accumulation and acidic tumor microenvironment (TME)-triggered release, Tz-Ir can synchronously realize efficient click-activation and precise membrane-localization via specific bioorthogonal metabolic glycoengineering technology. Upon US irradiation, in situ activated Tz-Ir can generate abundant ROS to destroy tumor cell membrane for a high-efficiency SDT. Moreover, for the first time, the maximized membrane damage is certified to evoke highly immunogenic PANoptosis (pyroptosis, apoptosis and necroptosis) of tumor cells, resulting in remarkably amplified tumor immunogenicity. The PANoptosis-boosted ICD effect can elicit robust systemic adaptive and innate antitumor immunity to effectively inhibit the growths of primary/distant tumors and lung metastasis. This tumor-specific membrane-targeting SDT modality based on bioorthogonal click activation presents an innovative strategy for precise and augmented tumor sono-immunotherapy.