蒲公英型异质纳米囊泡对肿瘤细胞表面的在体改造用于黑色素瘤免疫治疗研究

To solve the current problem of poor treatment effect induced by cell therapy for solid tumors, the development of a general technology, to remodel tumor cell surfaces in vivo and improve their ability to be recognized by the immune system, is of great significance. Based on the previous findings and experience aiming to immune evasion mechanisms of solid tumors, this project focuses on addressing three major problems, including (1) lack of tumor-associated antigens on tumor cell surfaces, (2) real-time monitoring difficulties in vivo, and (3) complicated immune microenvironments. A series of “dandelion-like heterogeneous nanovesicles” are constructed. These nanovesicles are composed of and self-assembled by amphipathic Au-Fe3O4 Janus nanoparticles in aqueous solutions. Tumor-associated antigen and immune checkpoint blocker are loaded on the surface and in the inner core of nanovesicles, respectively. They are used to enhance the antigen level on the surface of tumor cells in vivo, activate immune cells, and block the immune checkpoint. Utilizing the unique optical and magnetic properties of Janus nanoparticles, we plane to investigate the targeting ability of nanovesicles in tumors and their remodelling capability on tumor cell surfaces in vivo; reveal the relative mechanisms involved in the processes of cell surface remodeling and tumor treatment; reverse the immune microenvironments and subsequently enhance the immunotherapeutic effect of melanoma model. This project will provide new ideas, methods, and techniques for antitumor treatment strategies combining cell therapy and immunotherapy in the fields of material science and pharmacy.

为了解决目前细胞疗法对实体瘤治疗效果不佳的问题，发展通用技术，对肿瘤细胞表面实施在体改造，提高其被免疫系统识别的能力，具有重要意义。在前期研究结果和经验的基础上，本项目针对实体瘤免疫逃逸机制，聚焦（1）细胞表面肿瘤相关性抗原缺乏、（2）治疗过程中体内实时监测困难和（3）免疫微环境复杂这三大问题，构建一类“蒲公英型异质纳米囊泡”。该囊泡由两亲性双面Au-Fe3O4纳米颗粒在水溶液中自组装而成，其表面和内核分别负载肿瘤相关性抗原和免疫检查点阻断剂，用于在体水平的肿瘤细胞表面抗原增补、免疫细胞激活和免疫检查点阻断。利用双面纳米颗粒特异的光学和磁学性质，研究囊泡的瘤体靶向性和肿瘤细胞表面在体改造能力，揭示细胞改造和肿瘤治疗的相关机制，从多方面调控和逆转免疫微环境，从而提升黑色素瘤模型的免疫治疗效果。项目的实施将为细胞疗法和免疫疗法相结合的抗肿瘤治疗策略提供新的材料学和药学的思路、方法和技术。

在前期研究结果和经验的基础上，本项目针对目前细胞疗法对实体瘤治疗效果不佳的问题，聚焦实体瘤免疫逃逸机制，包括（1）细胞表面肿瘤相关性抗原缺乏、（2）治疗过程中体内实时监测困难和（3）免疫微环境复杂等，构建了一类“蒲公英型异质纳米囊泡”。该囊泡由两亲性双面Au-Fe3O4纳米颗粒在水溶液中自组装而成，在其表面负载能引发较强免疫反应的异种抗原，实现在体水平的肿瘤细胞表面抗原增补和免疫细胞激活。实验结果表明，具有蒲公英型结构的纳米囊泡（1）具有良好的肿瘤被动靶向能力和生物安全性；（2）可有效将异种抗原分子精确地锚定在肿瘤细胞表面；（3）通过ADCC机制导致肿瘤细胞裂解；（4）进而激发获得性免疫治疗。这种通过膜表面工程化的策略的独特之处在于：（1）表面工程化分子或器件不具有生物毒性，但能有效诱导肿瘤细胞死亡；（2）通过对肿瘤细胞非特异性的固有免疫机制诱导出特异性的获得性免疫治疗效果；（3）它是一种通用技术，“蒲公英型异质纳米囊泡”结构简单、可调控性强，系统中双亲性单元和异种抗原均可根据不同的治疗进行更改和替换。项目的实施为细胞疗法和免疫疗法相结合的抗肿瘤治疗策略提供了新的材料学和药学的思路、方法和技术。