三特异性Janus纳米颗粒的胞内可控制备与多效应肿瘤免疫治疗

Recent studies demonstrated that Immunotherapy is a promising method for cancer treatment. However, many patients do not have a good response to the current immunotherapy, because the tumor cells have many strategies to evade the immune surveillance. A therapy combined of different strategies, which can induce anti-tumor immunity and inhibit the tumor immune escape simultaneously, can effectively improve the effect of immunotherapy. Herein, we intend to explore the intracellular controllable asymmetric self-assembly technique, by using the metabolic regulation network in bacteria and synthetic biological. Based on this system, we will construct tri-specific Janus nanoparticles by using ferritin as chassis. This tri-specific Janus nanoparticle is directly asymmetric self-assembled by three different functionalized self-assembling ferritin subunits in E.coli. The resultant Janus nanoparticle can target to tumor cells, recruit the lymphocytes and inhibit the immune escape of tumor simultaneously in a same place. Using hepatocellular carcinoma (HCC) as a target, the tri-specific Janus nanoparticle will be introduced into HCC therapies, to induce multiple biological effects of immunotherapy, and finally achieve optimal therapy benefit. And we will investigate the relationship between the distribution of ligand ligands and the anti-tumor immune effect. This project will provide a feasible approach for constructing elaborate multifunctional Janus nanoparticles, and the strategy of tri-specific Janus nanoparticle mediated tumor immunotherapy should have board interests in tumor therapies.

免疫治疗是一种极具前景的肿瘤疗法。然而肿瘤的免疫逃逸能力，导致免疫治疗应答反应仅发生于部分患者。因此，发展多联免疫治疗方法，在诱导抗肿瘤免疫的同时抑制肿瘤免疫逃逸，能够有效的提高免疫治疗的效果。针对该问题，本申请拟利用铁蛋白纳米颗粒为载体，结合细菌内代谢调控网络和合成生物学手段，探索细菌内可控差量表达方法，使分别具有肿瘤细胞、T细胞和免疫监视点受体特异性结合功能的铁蛋白亚基在细菌内发生可控非对称自组装，一步法制备三特异性Janus纳米颗粒。该纳米颗粒同时具有靶向识别、T细胞招募和免疫逃逸抑制功能，整合了双特异性抗体和免疫监视点抑制的特点。以肝细胞癌为对象，将该颗粒用于肿瘤的免疫治疗，研究颗粒表面配体分布与多重抗肿瘤免疫效应引发的关系，探索多效应肿瘤免疫治疗的诱导机制。本项目的实施将为复杂功能Janus纳米颗粒的制备提供新的方法和思路，为发展高效肿瘤联合免疫治疗提供新的纳米技术路线。

本项目面向当前肿瘤免疫治疗中免疫应答不足的问题，利用细菌代谢网络调控系统建立细菌内可控非对称自组装技术，构建三特异性Janus纳米颗粒，发展多联免疫治疗方法，在诱导抗肿瘤免疫的同时抑制肿瘤免疫逃逸，能够有效的提高免疫治疗的效果。.在本研究实施过程中，成功的建立了基于代谢调控的细菌内非对称自组装纳米颗粒的制备技术，发展了具有稳定信号扩增能力的荧光增敏探针和大肠杆菌内人工“辅助模块”装配高二氧化碳固定效率羧化体；探索了三特异性Janus纳米颗粒的多种制备方法，但受限于蛋白可溶性表达问题，未能获得突破，近期在尝试一种基于酶促蛋白连接的方法来进行构建；利用上述研究中的技术成果，成功发展了能够增强抗原-抗体特异性结合力的3D生物探针，具有“干湿”界面特性的高性能催化纳米结构，以及高FRET率的长斯托克斯位移荧光纳米探针。.综上，该研究建立了一种新型细菌内自组装体可控构建技术，发展了具有复杂功能的自组装纳米结构理性设计方法，研究构建的纳米结构在病原检测、生物传感与活体成像方面具有重要的应用价值，部分技术已经或正在进行产业转化，并在新冠疫情期间得到了应用。

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