TROP2-aptamer/CD24-siRNA靶向纳米药物构建及三阴性乳腺癌成像和免疫-化疗协同治疗研究

三阴性乳腺癌（TNBC）是一种恶性程度极高的肿瘤，患者5年生存率不足15%。以免疫检查点抑制剂为代表的抗肿瘤免疫治疗的出现为TNBC治疗提供了一种全新的策略。然而，抗体类阻断剂不能特异性靶向肿瘤组织内的免疫细胞进行免疫调节，严重限制其治疗效果并易产生较大的毒副作用。利用新型的调控策略来阻断免疫检查点通路是近年来的研究热点。本课题拟借助RNA干扰技术沉默CD24基因，特异性阻断CD24/Siglec-10免疫检查点通路。通过构建一种新型TROP2-aptamer/CD24-siRNA靶向纳米药剂，用于TNBC精准成像和免疫治疗,并联同化疗药物，在体内促进肿瘤相关巨噬细胞吞噬作用的同时有效杀伤肿瘤细胞，实现免疫-化疗协同治疗。该研究结合多种前沿技术，利用RNA干扰技术精准阻断免疫检查点通路，实现核酸类和小分子药物的共同传递、精准释放，为抗肿瘤免疫治疗提供了新的思路。

Triple-negative breast cancer (TNBC) is one of the most lethal malignancies worldwide. The 5-year survival rate of TNBC patients is less than 15%. The emergence of immune checkpoint inhibitors (ICIs) for anti-tumor immunotherapy provides a brand-new strategy for TNBC treatments. However, blockers like antibodies cannot specifically target immune cells in tumor tissues for immune regulation, which limits their therapeutic effects and always induces immune-related adverse events. Recently, many studies paid more and more attention on the development of novel regulatory strategies to block immune checkpoint pathways. In this study, we intend to use RNA interference (RNAi) technology to knock down CD24 gene, leading to block the CD24/Siglec-10 immune checkpoint pathway. A novel TROP2-aptamer/CD24-siRNA targeting nanomedicine will be developed for imaging and immunotherapy of TNBC. We will combine the CD24-siRNA and chemotherapy to improve the synergistic effect of the immuno- and chemo-therapy by promoting the phagocytosis of tumor-associated macrophage and inducing tumor cell apoptosis. In addition, the modification with high-affinity TROP2-apatermer is capable of improving the targeting of the nanomedicine to primary and metastatic TNBC tumors. This study combines various advanced technologies to block the immune checkpoint pathway by RNAi technology, co-deliver nucleic acids and small molecular drugs, which is a new strategy for cancer immunotherapy.