Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, 266021, China.
Small. 2024 Oct;20(42):e2401397. doi: 10.1002/smll.202401397. Epub 2024 Jun 19.
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 (R)-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 R 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.
细胞焦亡作为一种炎症性细胞死亡方式，在激活炎症反应、逆转免疫抑制和增强抗肿瘤免疫方面发挥着关键作用。然而，如何有效地、精准地在肿瘤细胞中诱导细胞焦亡以增强抗肿瘤免疫治疗仍然存在挑战。在此，设计了一种 pH 响应性聚多巴胺（PDA）纳米团簇，即全氟碳（PFC）@辛基-精氨酸（R）-1-十六烷基胺（He）-卟啉（Por）@PDA-藤黄酸（GA）-环肽（R-P）@PDA-GC，通过双输入程序化级联治疗来增强光疗诱导的细胞焦亡和增强抗肿瘤免疫。简要地说，氧供体 PFC 被包裹在 R 连接的光敏剂 Por 和 He 胶束作为核心，然后加入 GA 和 cRGD 肽修饰的 PDA 壳，得到最终的 R-P@PDA-GC 纳米平台（NPs）。该 pH 响应性 NPs 通过 PFC 有效地缓解了肿瘤细胞的缺氧，并通过 GA 减轻了肿瘤细胞的耐热性。在双输入程序化照射下，R-P@PDA-GC NPs 可显著增加肿瘤细胞内活性氧的产生，通过 Caspase-1/GSDMD 途径引发细胞焦亡，并将大量炎症因子释放到 TME 中。这导致树突状细胞成熟，细胞毒性 CD8 T 和 NK 细胞大量浸润，免疫抑制性 Treg 细胞减少，从而增强了抗肿瘤免疫。
