聚合物囊泡组装体T细胞“背包”的功能化设计以及在实体瘤免疫治疗中的应用研究

免疫疗法是目前最受关注的肿瘤治疗手段，然而实体瘤致密的细胞外基质和免疫抑制微环境导致T细胞难以产生强效的杀伤。T细胞“背包”作为一种新型的纳米递送系统能够贴附在T细胞表面，并释放药物增强T细胞的功能。但是，能同时降解细胞外基质并改善免疫抑制微环境的“背包”系统尚未见报道。申请人前期工作提示，聚合物囊泡组装体作为T细胞“背包”能避免细胞内吞，还可递送多种药物并实现程序化控释。本项目首先设计制备分别包裹透明质酸酶和IL-21的聚合物囊泡，利用生物素-链霉亲和素体系形成组装体，通过anti-PD-1的修饰实现组装体对表达PD-1的T细胞的靶向识别和贴附，并对“背包”随T细胞浸润实体瘤时逐级响应金属蛋白酶和低氧信号的控释特性进行研究。通过胰腺癌3D类器官模型和体内荷瘤实验考察组装体“背包”的稳定性，对T细胞浸润和功能的促进作用及抗瘤效果。本项目将为纳米药物递送系统的实体瘤免疫治疗提供新思路。

Immunotherapy has received great attention in recent cancer therapy. However, for solid tumor, it becomes less efficacious and the cytotoxic activities of T cells are reduced, due to the dense extracellular matrix and immunosuppressive microenvironment. T cell “backpack” as a new emerging nano-delivery system facilitates its adherence to the cell surface and releases drugs to augment T cell function. Nonetheless, T cell “backpack” degrading extracellular matrix and reversing immunosuppressive microenvironment simultaneously has not been reported yet. The previous studies from the applicant suggest that polymersome assemblies enable the adherence to the cell surface, targeted delivery and programmable drug release, thus are ideal for T cell “backpack”. Here, we develop hyaluronidase-encapsulated and interleukin-21-encapsulated polymersomes, follow by their assembly through biotin-streptavidin interaction. The polymersome assemblies will be modified with an anti-PD-1 antibody, which recognizes the PD-1 biomarker on T cells, and adheres polymersome assemblies on the cell surface. The “backpack” together with T cell infiltrates the solid tumor, responses to the matrix metalloproteinase and hypoxia in the tumor microenvironment, and subsequently releases the loaded drugs. The release behaviors of T cell “backpack” will be investigated and the effect on the proliferation as well as the cytotoxicity of T cells will be demonstrated. Pancreas 3D organoids and mouse tumor models will be employed for evaluating the stability of T cell “backpack”, as well as the influence of T cell “backpack” on T cell infiltration and anti-tumor function. This project will provide a new strategy to enhance solid tumor immunotherapy with nano-delivery system.