功能化双特异性抗体囊泡用于肝癌免疫治疗

肝癌是全球发病率和死亡率最高的恶性肿瘤之一，寻找一种高效的肝癌治疗方法是当务之急。免疫疗法是一种新兴的肿瘤治疗策略，其中双特异性抗体（BsAbs）介导的T细胞重定向杀伤肿瘤细胞被认为是最有希望的肿瘤治疗策略。基于团队前期工作基础，本项目拟采用细胞膜定向展示和仿生自组装等技术，构建一种双特异性抗体介导的细胞膜衍生的纳米囊泡，探索仿生自组装行为及利用无创多模态成像方法阐明其作用机制。通过将双特异性抗体纳米化，通过调控囊泡尺寸，使肿瘤细胞-BsAbs-T细胞之间形成的免疫突触间隙大小及空间结构可促进T细胞的重定向作用，从而增强双特异性抗体的肿瘤杀伤活性。本项目拟将细胞膜囊泡载体与肿瘤免疫治疗紧密结合，有效提高抗体、造影剂/药物、免疫细胞等的靶向性，实现体内药物缓释作用，最大程度上发挥二者结合的优势，有望为肿瘤的免疫治疗提供一种新的无细胞疗法，为抗体药物研究及肿瘤免疫治疗带来新的突破。

Hepatocellular carcinoma (HCC) is one of the malignant tumors with the highest morbidity and mortality in the world. There is an urgent need to develop more effective therapeutic strategies and agents for HCC treatment. Immunotherapy have emerged as potentially effective treatments for patients with HCC. Among them, T cell redirection mediated by bispecific antibodies (BsAbs) is a promising cancer therapy. Based on the preliminary work of our group, this project intends to design and prepare a novel cellular nanovesicles that can present BsAbs with innovative technologies, such as directional membrane display and biomimic self-assembly. Furthermore, the biomimetic self-assembly behavior and a non-invasive multimodal imaging method would also be explored to evaluate the mechanism. Through making BsAbs in nano-scale, spacing and spatial structural characteristics of the immunological synapses (ISs) would be changed with the size of these vesicles, which could contribute to efficient T cell redirection. This project will effectively improve the targeting of antibodies、 contrast agents / drugs、 immune cells, realize good sustained drug release effect, and show unequaled cooperative effects in nanomedicine and immunotherapy. Together, this study will not only provide a general and versatile approach for the development of a new class of cell-free therapy, but also bring a new break-through for the research of antibody drugs and immunotherapy.