靶向并激活肿瘤相关巨噬细胞NLRP3炎性小体通路的纳米粒设计及抗肿瘤作用研究

The main barrier of tumor immunotherapy is the immunosuppressive tumor microenvironment. Tumor-associated macrophages (TAMs) play an important role in the formation and maintenance of tumor microenvironment. The study of NLRP3 inflammasome inspires us a new strategy for targeting TAMs and reprogramming the tumor microenvironment by means of activating the NLRP3 inflammasome pathway.The activation of NLRP3 inflammasome needs two signals: the first signal is mediated by TLRs and the second signal is mediated by NLRs, once activated, resulting in pyroptotic cell death. Nowadays, some nanoparticles have been reported to induce inflammasome activation through activating the NLRs. Therefore, we firstly intend to screen out the best nanoparticles for effeciently and specificly activating the NLRs of TAMs.Then we will couple a TLR agonist on the surface of nanoparticles.The prepared nanoparticles could gather in the tumor and release the TLR agonist responsing to the tumor microenvironment. The TLR agonist and nanoparticle could activate the NLRP3 inflammasome of TAMs , which could reprogram the tumor microenvironment and activate antitumor immune response. This study will explore whether the activation of NLRP3 inflammasome pathway of TAMs could induce effencient antitumor immune response, in order to provide new ideas for tumor immunotherapy, and provide evidence for designing nano-medicines for tumor immunotherapy.

肿瘤免疫治疗的主要屏障是肿瘤的免疫抑制性微环境。肿瘤相关巨噬细胞（TAMs）在塑造及维持肿瘤微环境中发挥重要作用。本项目设想激活TAM的NLRP3炎性小体通路可能是调控TAM、重塑肿瘤微环境的钥匙。NLRP3炎性小体的激活需要Toll样受体（TLRs）介导的第一信号及NOD样受体（NLRs）介导的第二信号的同时激活，激活后导致TAM焦亡。据报道有些纳米粒可激活NLRs，但不能激活TLRs。本项目在筛选到高效特异性激活TAM的NLRs的纳米粒基础上，将TLRs激活剂与纳米粒偶联，构建双激活纳米粒。该纳米粒被动靶向至TAMs，响应肿瘤微环境释放出TLRs激活剂，与激活NLRs的纳米粒共同激活NLRP3炎性小体，重塑肿瘤微环境，启动抗肿瘤免疫反应。本研究将深入探讨激活TAMs 的NLRP3炎性小体通路诱发抗肿瘤免疫反应的可行性，为肿瘤免疫治疗提供新思路，为研发肿瘤免疫治疗用纳米药物提供依据。

纳米递送系统在多种疾病中具有广泛的应用。修饰过的纳米材料本身可作为有效的免疫调控剂，调控机体免疫反应；亦可作为递送载体将药物靶向递送至疾病部位；从而实现对肿瘤等疾病的治疗。在本项目中，我们构建了多种纳米递送系统，在动脉粥状硬化、肿瘤、乙肝感染中均起到了一定的治疗效果。我们成功构建了一种包含磷脂酰丝氨酸和RGD双靶头的脂质体，使用该脂质体成功将抗炎药物吡格列酮靶向递送至动脉粥状硬化斑块部位，缓解了动脉粥状硬化症状；成功合成了一种铁螯合的黑色素养纳米颗粒，在原发性肿瘤及转移瘤模型中具有良好的重塑巨噬细胞极化及抗肿瘤效果；成功构建了肝细胞特异、多靶头CRISPR/Cas9小环质粒系统，配合新开发的阳离子脂质体，在体内外乙肝模型中均起到了良好的治疗效果