携anti-miR-33双靶向纳米泡巨噬细胞内释药调控动脉粥样硬化炎症的研究

anti-miR-33可通过抑制动脉粥样硬化（AS）斑块内巨噬细胞中miR-33的表达增强巨噬细胞胆固醇外排及胞葬作用，从而抑制斑块内炎症反应，实现对AS的治疗。但传统给药方式将对全身miR-33进行非特异性抑制并导致严重的代谢功能障碍。如何实现anti-miR-33对AS斑块内巨噬细胞的精准干预是现阶段亟待解决的核心问题。课题组在前期研究中利用UTMD技术实现了治疗因子的局部控释，但是该方法的靶向释药过程发生在细胞外，仍然存在部分治疗因子脱靶的现象。因此项目组认为，实现治疗因子在靶细胞内的释放是进一步提高靶向治疗精准性的关键。为实现该目标，本项目拟通过在脂质纳米泡表面携带透明质酸、适配子PM1以及anti-miR-33的方式构建分阶段寻靶载体，靶向识别AS斑块内巨噬细胞并通过巨噬细胞的吞噬作用完成anti-miR-33的胞内释放从而改善细胞功能、抑制炎症，实现AS在细胞水平的精准治疗。

It has been well elucidated that anti-miR-33 could suppresses inflammation progress in atherosclerosis by down-regulating miR-33, improving cholesterol efflux and efferocytosis of macrophages in atherosclerotic plaques. However, evidence was shown that administration of anti-miR-33 through conventional manner will led to a non-specific inhibition of miR-33, and ultimately cause severe metabolic dysfunction. In this context, methods can realize a precise delivery of anti-mir-33 to macrophages in atherosclerotic plaques are on a desperate demand. In our previous studies, we have managed a site-specific deliver of therapeutic factor under the aid of UTMD technique. However, we found that the “drug release” procedure mediated by UTMD occurs outside the cell and there are still a considerable amount of therapeutic factors miss the target. Therefore, we hypothesis that release therapeutic factors inside the targeted cells is the key to further improve the accuracy of targeted therapy. To achieve this goal, we fabricate a kind of lipid nanobubbles carrying hyaluronate, aptamer PM1 and anti-miR-33 to realize a pinpoint recognition of macrophages in atherosclerotic plaques through a multistage-targeting strategy. Then, accomplish intracellular release of anti-miR-33 through phagocytosis of macrophages to improve cell function and inhibit inflammation, and provide an novel anti-atherosclerosis strategy.