基于靶向超声纳米微泡介导的si-PD-L1/si-siglec-15与CAT协同增强肿瘤精准免疫诊疗的研究

免疫治疗是最有希望实现肿瘤治愈的有效手段，但存在应答率较低及自身不良反应等问题，探索新的治疗靶点及靶向性方案是关键，多功能超声纳米微泡可为提升免疫诊疗提供重要载体。我们前期研究发现，羧甲基壳聚糖纳米微泡具有两性特征，携载药物/基因能够增敏肿瘤放化疗效果，实现可视化精准诊疗；超声辐照联合纳米微泡能够提高ROS水平，可为乏氧微环境改善提供充足底物；基因纳米技术构建的3WJ-pRNA呈现三叶草构像，可实现多功能修饰或多基因携载。据此，本项目结合PD-L1、Siglec-15免疫检查点分子的表达互补性，以及CAT分解ROS生成氧气的特性，拟通过3WJ-pRNA技术，制备可携载抑制基因si-PD-L1、si-Siglec-15和CAT的新型多功能叶酸靶向纳米微泡，实现双重免疫检查点干预联合乏氧微环境改善协同增强肿瘤免疫诊疗的目的。本项目的实施将为超声纳米微泡介导的肿瘤精准免疫诊疗提供新策略。

Immunotherapy is the promising and effective strategy for tumor cure, but there are some problems such as low-response and adverse reactions, so it is necessary to explore new targets and targeted programs, multifunctional ultrasound nanobubbles can provide an important carrier for improving immunotherapy. We have previously found that carboxymethyl chitosan nanobubbles have the observable amphoteric characteristic, which carrying drug/gene could enhance the effect of radiotherapy and chemotherapy, then realize the visualized targeted theranostic, and also confirmed that ultrasound irradiation combined with nanobubbles could improve the ROS level in tumor, thus provide sufficient substrate for improving oxygen, and also demonstrated that the 3WJ-pRNA constructed by gene nanotechnology shows the structure of clover, which can carry multiple genes. Based on our previous achievements, and considering the complementary expression of PD-L1 and Siglec-15, as well as the phenomenon of oxygen production catalyzed by CAT, we will design and construct a novel kind of multifuntional folate targeted nanobubbles through 3WJ-pRNA gene nanotechnology, which posess the abilities of loading si-PD-L1, si-Siglec-15 and CAT. The purposes of this project is to verify the value of these new nanobubbles in enhancing the effectiveness of tumor immunotherapy through intervening double immunocheckpoints and improving the hypoxic microenvironment. The accomplishment of this project will provide a new way for ultrasound nanobubble-mediated tumor precise immunotherapy.