Reconstituted high-density lipoproteins (rHDLs) hold promise as nanocarriers for atherosclerosis-targeted delivery, with biofunctions typified by mediating cholesterol efflux. The paradox is how rHDL offloads the delivered drugs into atherosclerotic foam cells, while simultaneously transferring cholesterol out of cells. Herein, simvastatin-loaded discoidal rHDL (ST-d-rHDL), constructed based on established paradigms, was employed to investigate its basic trafficking mechanism in foam cells. As proved, ST-d-rHDL was resecreted via lysosomal and Golgi apparatus-recycling endosome-mediated pathways following clathrin-mediated endocytosis. And the resecretion ratio reached 60% within 6-h chase with excessive ST-d-rHDLs. During the rHDL resecretion, 39% of cellular cholesterol efflux was detected, accompanied by 85% of the encapsulated cargo released intracellularly. Furthermore, the recycling rate was demonstrated to be promoted by smaller rHDL size and higher cellular lipid contents. Collectively, endocytic recycling confers the synergism in ST-d-rHDL to coordinate cholesterol efflux and intracellular drug release, providing new insights into design of biofunctional rHDL.

重建的高密度脂蛋白 (rHDL) 有望作为动脉粥样硬化靶向递送的纳米载体，其生物功能以介导胆固醇流出为代表。悖论是 rHDL 如何将递送的药物卸载到动脉粥样硬化泡沫细胞中，同时将胆固醇转移出细胞。输入加载辛伐他汀的盘状 rHDL (ST-d-rHDL)，基于已建立的范式构建，用于研究其在泡沫细胞中的基本贩运机制。经证明，ST-d-rHDL 通过溶酶体和高尔基体循环内体介导的途径在网格蛋白介导的内吞作用后重新分泌。并且在ST-d-rHDLs过多的情况下，6小时内的再分泌率达到60%。在 rHDL 再分泌过程中，检测到 39% 的细胞胆固醇流出，伴随着 85% 的封装货物在细胞内释放。此外，证明更小的 rHDL 大小和更高的细胞脂质含量促进了回收率。总的来说，内吞循环赋予 ST-d-rHDL 协同作用以协调胆固醇流出和细胞内药物释放，为生物功能 rHDL 的设计提供了新的见解。