Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215006, P. R. China.
College of Pharmaceutical Sciences, Soochow University, Suzhou, 215006, P. R. China.
Adv Healthc Mater. 2024 Sep;13(23):e2400784. doi: 10.1002/adhm.202400784. Epub 2024 Jun 27.
Immunotherapy has emerged as a powerful weapon against lung cancer, yet only a fraction of patients respond to the treatment. Poly(I:C) (PIC) effectively triggers both innate and adaptive immunity. It can also induce immunogenic cell death (ICD) in tumor cells. However, its efficacy is hindered by its instability in vivo and limited cellular uptake. To address this, PIC is encapsulated in cRGD-functionalized polymersomes (t-PPIC), which significantly increases its stability and uptake, thus activating dendritic cells (DCs) and inducing apoptosis of lung tumor cells in vitro. In a murine LLC lung tumor model, systemic administration of t-PPIC effectively suppresses tumor growth and leads to survival benefits, with 40% of the mice becoming tumor-free. Notably, t-PPIC provokes stronger apoptosis and ICD in tumor tissue and elicits a more potent stimulation of DCs, recruitment of natural killer (NK) cells, and activation of CD8 T cells, compared to free PIC and nontargeted PPIC controls. Furthermore, when combined with immune checkpoint inhibitors or radiotherapy, t-PPIC amplifies the antitumor immune response, resulting in complete regression in 60% of the mice. These compelling findings underscore the potential of integrin-targeted polymersomal PIC to enhance antitumor immunity by simultaneously inducing ICD and systemic immune activation.
免疫疗法已成为对抗肺癌的有力武器，但只有一小部分患者对治疗有反应。聚肌胞苷酸（PIC）能有效触发固有和适应性免疫。它还可以诱导肿瘤细胞发生免疫原性细胞死亡（ICD）。然而，其疗效受到体内不稳定性和有限的细胞摄取的限制。为了解决这个问题，PIC 被封装在 cRGD 功能化聚合物囊泡（t-PPIC）中，这显著提高了其稳定性和摄取率，从而激活树突状细胞（DC）并诱导体外肺肿瘤细胞凋亡。在小鼠 LLC 肺癌肿瘤模型中，全身性给予 t-PPIC 能有效抑制肿瘤生长并带来生存获益，其中 40%的小鼠肿瘤完全消失。值得注意的是，与游离 PIC 和非靶向 PPIC 对照相比，t-PPIC 在肿瘤组织中引发更强的凋亡和 ICD，并引发更强的 DC 刺激、自然杀伤（NK）细胞募集和 CD8 T 细胞激活。此外，当与免疫检查点抑制剂或放疗联合使用时，t-PPIC 增强了抗肿瘤免疫反应，使 60%的小鼠肿瘤完全消退。这些引人注目的发现强调了整合素靶向聚合物囊泡 PIC 通过同时诱导 ICD 和全身免疫激活来增强抗肿瘤免疫的潜力。
