基于细胞膜修饰的自组装靶向仿生纳米材料用于肿瘤免疫治疗的研究

Tumor immunotherapy uses the innate activity of the immune system to control and eliminate tumor cells without attacking normal cells. Clinical studies have shown that blocking the PD-1/PD-L1 pathway can effectively achieve tumor immunotherapy. However, there is no effective gene vector currently. In this study, the cancer cell membrane fusion specific targeting peptide RGD was used as the outer layer material, and the drug/gene carrier was integrated into the inner layer material by self-assembly technology to construct a self-assembly targeting biomimetic nano-material CRICG based on cell membrane modification. The study plans to use the CRICG system to carry PD-L1 siRNA, chemotherapeutic drugs and immunosuppressive agents (NLG919) for immune regulation and tumor targeted therapy through stepwise response and release. We will evaluate the structure, morphology, stimuli-responsive ability, gene/drug performance, cytotoxicity, tumor specificity, immune regulation ability and anti-tumor effect of CRICG system in vitro and in vivo. The CRICG system will achieve the regulation of the PD-1/PD-L1 pathway at the gene level, providing a practical basis for the development of functional vectors.

肿瘤免疫治疗是一种利用免疫系统的固有活性来控制和消除肿瘤细胞而不攻击正常细胞的疗法。临床研究表明阻断PD-1/PD-L1通路能够有效地实现肿瘤的免疫治疗，然而目前缺乏有效的载体。本研究拟采用癌细胞膜融合特异性靶向肽RGD作为外层材料，通过自组装技术整合药物/基因载体构成内层材料，构建一种基于细胞膜修饰的自组装靶向仿生纳米材料CRICG。研究拟用CRICG系统携带PD-L1 siRNA、化疗药物和免疫抑制剂（NLG919），通过逐级响应和释放进行免疫调控和肿瘤的靶向治疗。并对CRICG进行结构、形态、环境响应性能表征，载基因和药物性能评价，靶向性评价，细胞毒性评价；在体内外层面研究CRICG体系的免疫调控能力和抗肿瘤疗效。CRICG体系将实现在基因水平调控PD-1/PD-L1通路，为开发功能性载体提供实践依据。

肿瘤免疫治疗是一种利用免疫系统的固有活性来控制和消除肿瘤细胞而不攻击正常细胞的疗法。临床研究表明免疫检查点阻断能够有效地实现肿瘤的免疫治疗，然而目前缺乏有效的载体。我们设计了一种癌细胞膜包裹的仿生纳米粒子，以进一步增强光热治疗后原发性肿瘤和远端转移肿瘤的免疫抑制。癌细胞膜的包裹赋予纳米粒子长循环时间和同源靶向等优点。制备的仿生纳米粒子可以运载药物聚集到肿瘤部位，从而增强抗肿瘤干预效果。此外，为了探索光热协同免疫治疗的机制，分别在4T1细胞和4T1荷瘤小鼠中检测了仿生纳米粒子诱导的免疫原性死亡、树突状细胞的成熟、细胞毒T淋巴细胞的瘤内浸润和免疫抑制肿瘤微环境的影响。我们还通过肿瘤预防实验评估了仿生纳米粒子对肿瘤复发的影响。此研究为开发功能性载体提供实践依据。