mRNA/碳酸钙递送载体的构建、优化及其用于工程化外泌体型肿瘤免疫治疗药物的研究

肿瘤免疫治疗可激活机体免疫系统对肿瘤细胞的特异性识别和杀伤，是极具前景的新型肿瘤治疗手段。现有的免疫治疗策略多侧重于提升细胞免疫应答水平，激活更多的杀伤性免疫细胞，而忽视了肿瘤部位免疫抑制微环境的问题，导致免疫治疗效果大打折扣。本项目拟通过实验-模拟相结合的手段，按需设计出具有特定介尺度结构和最优构效关系的肿瘤mRNA/碳酸钙递送体系（mRNA/CaCO3），对抗原提呈细胞（APC）进行重编程，借助碳酸钙在酸性溶酶体内溶解产生的二氧化碳气压，胀破溶酶体，实现肿瘤mRNA在APC细胞质中的内源性表达，从而将APC转化为兼具APC功能与肿瘤抗原表达的工程化细胞。其分泌的工程化外泌体作为肿瘤免疫治疗药物，可利用其纳米粒径和肿瘤趋化分子实现淋巴结和肿瘤的双重靶向，并利用其上携带的免疫激活信号实现淋巴结内免疫激活和肿瘤部位微环境改善的双效协同，可最大限度地提升抗肿瘤效果，极具临床应用潜力。

Tumor immnuotherapy triggers immune system to recognize and attack tumor cells, providing a promising approach to inhibit tumor growth. The majority of current immunotherapeutic strategies only aimed to promote cellular immune response and overlooked the immunosuppressive tumor microenvironment in tumor site, leading to the diminishment of therapeutic effect. Through adopting the combination method of experimentation & computer-simulation, an on-demand tumor mRNA/calcium carbonate delivery system (mRNA/CaCO3) with optimal structure-activity relationship will be developed for the reprogramming of antigen presenting cell (APC). Inside the acidic lysosomes of APC, CaCO3 will dissolve and accompany by eruptible CO2 generation. The increasing pressure inside lysosome will result in lysosome deconstruction. Then, the doped mRNA cargo will be subsequently released into cytoplasm, where the tumor antigens can be translated from mRNA, resulting in the transformation of engineered APC-tumor cells. Naturally, their derived exosomes will inherit the hybrid properties of APC & tumor cell. Owing to the nano-size and tumor chemotactic molecules expression, engineering exosomes will hold dual-targeting ability towards lymph node & tumor. Furthermore, depending on the carried immune-activating molecules, they will exert synergistic effect of immunity-activation & tumor microenvironment regulation and induce excellent tumor therapeutic efficacy, providing promising potential for clinical application.