Abstract：
Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti-tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti-tumor immunotherapy. Herein, a pH-responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo-arginine (R8)-1-Hexadecylamine (He)-porphyrin (Por)@PDA-gambogic acid (GA)-cRGD (R-P@PDA-GC), is rationally design to augment phototherapy-induced pyroptosis and boost anti-tumor immunity through a two-input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R8 linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R-P@PDA-GC nanoplatforms (NPs). The pH-responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two-input programmed irradiation, R-P@PDA-GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase-1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8+ T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti-tumor immunity.
摘要：
焦亡,炎症细胞死亡，在激活炎症反应中起关键作用，逆转免疫抑制和增强抗肿瘤免疫力。然而,关于如何在肿瘤细胞中有效和精确地诱导焦亡以扩增抗肿瘤免疫疗法仍然存在挑战。在这里，pH响应型聚多巴胺（PDA）纳米簇，全氟化碳(PFC)@八精氨酸(R8)-1-十六胺(He)-卟啉(Por)@PDA-藤黄酸(GA)-cRGD(R-P@PDA-GC),通过两输入程序级联疗法合理设计以增强光疗诱导的焦亡并增强抗肿瘤免疫力。简而言之，氧供体PFC封装在R8连接的光敏剂Por和He胶束作为核心，然后掺入GA和cRGD肽修饰的PDA壳，产生最终的R-P@PDA-GC纳米平台(NPs)。pH响应性NP通过经由PFC递送氧来有效地缓解缺氧,并且通过GA减轻肿瘤细胞中的耐热性。在双输入程序照射时，R-P@PDA-GCNP显着增强肿瘤细胞内活性氧的产生，通过Caspase-1/GSDMD途径触发细胞凋亡，并释放多种炎症因子进入TME。这导致树突状细胞的成熟，细胞毒性CD8+T和NK细胞的强大浸润，免疫抑制Treg细胞的减少，从而增强抗肿瘤免疫力。
