College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, South Korea.
Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea.
Sci Adv. 2021 Feb 26;7(9). doi: 10.1126/sciadv.abf4398. Print 2021 Feb.
Ionizable lipid nanoparticles (LNPs) have been widely used for in vivo delivery of RNA therapeutics into the liver. However, a main challenge remains to develop LNP formulations for selective delivery of RNA into certain types of liver cells, such as hepatocytes and liver sinusoidal endothelial cells (LSECs). Here, we report the engineered LNPs for the targeted delivery of RNA into hepatocytes and LSECs. The effects of particle size and polyethylene glycol-lipid content in the LNPs were evaluated for the hepatocyte-specific delivery of mRNA by ApoE-mediated cellular uptake through low-density lipoprotein receptors. Targeted delivery of RNA to LSECs was further investigated using active ligands. Incorporation of mannose allowed the selective delivery of RNA to LSECs, while minimizing the unwanted cellular uptake by hepatocytes. These results demonstrate that engineered LNPs have great potential for the cell type-specific delivery of RNA into the liver and other tissues.
可离子化脂质纳米颗粒 (LNPs) 已广泛用于将 RNA 治疗药物递送至体内的肝脏。然而，开发用于将 RNA 选择性递送至特定类型的肝细胞（如肝细胞和肝窦内皮细胞 (LSEC)）的 LNP 制剂仍然是一个主要挑战。在这里，我们报告了用于将 RNA 靶向递送至肝细胞和 LSEC 的工程化 LNPs。通过载脂蛋白 E 介导的通过低密度脂蛋白受体的细胞摄取，评估了 LNPs 中颗粒大小和聚乙二醇脂质含量对 mRNA 的肝细胞特异性递送的影响。使用活性配体进一步研究了 RNA 递送至 LSEC 的靶向性。甘露糖的掺入允许 RNA 选择性递送至 LSEC，同时最大限度地减少肝细胞的非特异性摄取。这些结果表明，工程化 LNPs 具有将 RNA 递送至肝脏和其他组织的细胞类型特异性的巨大潜力。
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