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.

中文翻译：

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膜锚定可点击铱 (III) 纳米声敏剂原位诱发全视下，用于增强肿瘤声免疫治疗

精确和增强的肿瘤声免疫治疗迫切需要开发具有卓越声动力活性和免疫原性细胞死亡（ICD）诱导能力的可激活“关断”声敏剂。在此，一种膜锚定可点击铱 (III) 纳米声敏剂经过精心设计，可引发肿瘤特异性 PANoptosis，从而增强声动力治疗 (SDT) 和放大免疫激活。开发了一种可点击激活的四嗪功能化铱（III）声敏剂Tz-Ir，具有I/II型活性氧（ROS）生成能力，并进一步封装到交联人血清白蛋白（HSA）中形成酸响应纳米声敏剂HSA @Tz-Ir。经过肿瘤靶向积累和酸性肿瘤微环境（TME）触发释放后，Tz-Ir可以通过特定的生物正交代谢糖工程技术同步实现高效的点击激活和精确的膜定位。在US照射下，原位激活的Tz-Ir可以产生丰富的ROS来破坏肿瘤细胞膜，从而实现高效的SDT。此外，首次证明最大的膜损伤会引起肿瘤细胞的高度免疫原性全凋亡（细胞焦亡、细胞凋亡和坏死性凋亡），从而显着增强肿瘤免疫原性。 PANoptosis增强的ICD效应可以引发强大的全身适应性和先天抗肿瘤免疫，从而有效抑制原发/远处肿瘤的生长和肺转移。这种基于生物正交点击激活的肿瘤特异性膜靶向 SDT 模式为精确和增强的肿瘤声免疫治疗提供了一种创新策略。