载 DOX·PD-L1 siRNA 复合物的 GE11 修饰羧甲基壳聚糖胶束用于联合 ICD 和免疫逃逸抑制以对抗肿瘤。
GE11-modified carboxymethyl chitosan micelles to deliver DOX·PD-L1 siRNA complex for combination of ICD and immune escape inhibition against tumor.
机构信息
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China; Department of Pharmacology, School of Basic Medicine, Jining Medical University, Jining, Shandong 272000, China.
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
出版信息
Carbohydr Polym. 2023 Jul 15;312:120837. doi: 10.1016/j.carbpol.2023.120837. Epub 2023 Mar 24.
Programmed cell death-ligand 1 (PD-L1) small interfering RNA (siRNA) achieves tumor immunotherapy by restoring the immune response of T cells, but the efficacy of PD-1/PD-L1 monotherapy is relatively low. While immunogenic cell death (ICD) can improve the response of most tumors to anti-PD-L1 and enhance tumor immunotherapy. Herein, a targeting peptide GE11-functionalized dual-responsive carboxymethyl chitosan (CMCS) micelle (G-CMssOA) is developed for simultaneous delivery of PD-L1 siRNA and doxorubicin (DOX) in a complex form of DOX·PD-L1 siRNA (D&P). The complex-loaded micelles (G-CMssOA/D&P) have good physiological stability and pH/reduction responsiveness, and improve the intratumoral infiltration of CD4 and CD8 T cells, reduce Tregs (TGF-β), and increase the secretion of immune-stimulatory cytokine (TNF-α). The combination of DOX-induced ICD and PD-L1 siRNA-mediated immune escape inhibition significantly improves anti-tumor immune response and inhibits tumor growth. This complex delivery strategy provides a new approach for effectively delivering siRNA and enhancing anti-tumor immunotherapy.
程序性细胞死亡配体 1（PD-L1）小干扰 RNA（siRNA）通过恢复 T 细胞的免疫反应来实现肿瘤免疫治疗，但 PD-1/PD-L1 单药治疗的疗效相对较低。而免疫原性细胞死亡（ICD）可以提高大多数肿瘤对抗 PD-L1 的反应，并增强肿瘤免疫治疗。在此，开发了一种靶向肽 GE11 功能化的双响应羧甲基壳聚糖（CMCS）胶束（G-CMssOA），用于以 DOX·PD-L1 siRNA（D&P）的复杂形式同时递送 PD-L1 siRNA 和多柔比星（DOX）。负载复合物的胶束（G-CMssOA/D&P）具有良好的生理稳定性和 pH/还原响应性，可提高 CD4 和 CD8 T 细胞在肿瘤内的浸润，减少 Tregs（TGF-β），并增加免疫刺激性细胞因子（TNF-α）的分泌。DOX 诱导的 ICD 与 PD-L1 siRNA 介导的免疫逃逸抑制的联合作用显著改善了抗肿瘤免疫反应并抑制了肿瘤生长。这种复杂的递药策略为有效递送 siRNA 和增强抗肿瘤免疫治疗提供了一种新方法。
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