State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China.
Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Nano Lett. 2024 May 15;24(19):5690-5698. doi: 10.1021/acs.nanolett.4c00376. Epub 2024 May 3.
Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.
长期肿瘤饥饿可能是通过剥夺营养来提高抗肿瘤免疫反应的一种潜在策略。然而，由于免疫细胞迁移途径的阻断，将长期饥饿疗法与免疫疗法相结合往往效果有限。在此，通过光激活形成细胞外动态水凝胶来压缩血管，首次建立了一种智能血流调节剂 (BFR)，可以诱导长期肿瘤饥饿，在不影响免疫细胞迁移途径的情况下在肿瘤细胞中引发代谢应激。通过利用丙烯酰胺改性纳米光敏剂 (HMMAN) 和可生物降解的明胶甲基丙烯酯 (GelMA)，开发的细胞外水凝胶通过酶降解动态调节血流。此外，负载到 HMMAN 中的 aPD-L1 持续阻断免疫检查点。系统实验表明，免疫检查点阻断 (ICB) 和 BFR 诱导的代谢应激 (BIMS) 的联合应用通过重塑肿瘤免疫原性景观和增强抗肿瘤免疫反应，显著延缓了 Lewis 肺癌和乳腺癌的进展。
