Reduction of lipoprotein uptake by macrophages and stimulation of cholesterol efflux are two essential steps required for atherosclerotic plaque regression. We used the optimized mannose-functionalized dendrimeric nanoparticle (mDNP)-based platform for macrophage-specific delivery of therapeutics to simultaneously deliver SR-A siRNA (to reduce LDL uptake) and LXR ligand (LXR-L, to stimulate cholesterol efflux) – a novel “Two-pronged” approach to facilitate plaque regression. mDNP-mediated delivery of SR-A siRNA led to a significant reduction in SR-A expression with a corresponding decrease in uptake of oxLDL. Delivery of LXR-L increased expression of ABCA1/G1 and cholesterol efflux. Combined delivery of siRNA and LXR-L led to a significantly greater decrease in macrophage cholesterol content compared to either treatment alone. Administration of this in vitro optimized formulation of mDNP complexed with SR-A-siRNA and LXR-L (Two-pronged complex) to atherosclerotic LDLR−/− mice fed western diet (TD88137) led to significant regression of atherosclerotic plaques with a corresponding decrease in aortic cholesterol content.

减少巨噬细胞对脂蛋白的摄取和刺激胆固醇流出是动脉粥样硬化斑块消退所需的两个重要步骤。我们使用基于优化的甘露糖功能化树枝状纳米粒子 (mDNP) 的平台进行巨噬细胞特异性治疗药物的递送，以同时递送 SR-A siRNA（以减少 LDL 摄取）和 LXR 配体（LXR-L，以刺激胆固醇流出）——新颖的“双管齐下”方法促进斑块消退。 mDNP 介导的 SR-A siRNA 递送导致 SR-A 表达显着减少，并相应减少 oxLDL 的摄取。 LXR-L 的递送增加了 ABCA1/G1 的表达和胆固醇流出。与单独治疗相比，联合递送 siRNA 和 LXR-L 可使巨噬细胞胆固醇含量显着降低。将这种与 SR-A-siRNA 和 LXR-L（双管齐下复合物）复合的 mDNP 体外优化制剂给予喂食西方饮食的动脉粥样硬化 LDLR−/− 小鼠 (TD88137)，导致动脉粥样硬化斑块显着消退，并相应减少主动脉胆固醇含量。