多功能TAM靶向STAT3-siRNA/CpG递送系统调控TAM（M2→M1）及其作用机制研究

TAM在肿瘤生长、侵袭与迁移和免疫抑制中扮演重要作用，是肿瘤免疫治疗的重要靶细胞。本课题拟通过pHe敏感材料和CD206配体修饰的磷脂包覆磷酸钙纳米粒，用于TAM靶向核酸递送。该载体到达肿瘤弱酸性环境时，暴露巨噬细胞靶向配体，被TAM特异性内吞，在体内实现TAM靶向递送。. 内吞进入TAM的核酸递送系统在溶酶体中溶解释放核酸，其中CpG激活M1型信号通路，而STAT3-siRNA则下调M2型相关基因表达降低促瘤功能，调控肿瘤免疫抑制微环境。选用不同肿瘤细胞荷瘤模型，考察评价该TAM核酸靶向递送系统用于肿瘤免疫治疗的能力。. 在此基础上，本研究将采用多学科交叉手段对该递送系统在肿瘤内的相关递送过程及免疫作用的分子机制开展较为深入和系统的研究，以期对肿瘤免疫治疗及其研究提供思路和借鉴。无疑本研究的学术价值和科学意义较大。因此该项目具有新颖性、前瞻性、探索性。

Tumor assoicated macrophages foster tumor progression via angiogenesis, invasion and metastasis, and direct/ indirect immunosupression, suggesting TAMs are potential targers for cancer therapy. pH sensitive and CD206 ligands modified lipid coated calcium phosphonate nanoparticles were construct for necliec acid targeted delivery to TAMs in vivo. The nanoparticles were uptaked into macrophages mediated by exposed CD206 ligands after shield detachment because of weak acidic environment in tumor. . The vectors released necleic acid due to calcium phosphonate dissolution in lyosomes, where CpG activates M1 related signaling pathway and STAT3-siRNA silences M2-releated protumoral gene expression, regulate tumor immunosuppressive microenvironment. The antitumor effects were evaluated in different tumor models. . Furthermore, multidisciplinary study on the transportation and molecular mechanism of the vectors within tumor will be intensively explored, which is expected to lay foundation for tumor immunotherapy and research. There is no doubt that the research is of academic and scientific significance. Therefore, the study is novel, forward-looking and exploratory.