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.

可电离脂质纳米颗粒 (LNP) 已广泛用于将 RNA 治疗剂体内递送至肝脏。然而，主要挑战仍然是开发用于将 RNA 选择性递送到某些类型的肝细胞中的 LNP 制剂，例如肝细胞和肝窦内皮细胞 (LSEC)。在这里，我们报告了用于将 RNA 靶向递送到肝细胞和 LSEC 中的工程化 LNP。通过低密度脂蛋白受体通过 ApoE 介导的细胞摄取，评估了 LNP 中颗粒大小和聚乙二醇脂质含量对肝细胞特异性 mRNA 递送的影响。使用活性配体进一步研究了 RNA 向 LSEC 的靶向递送。甘露糖的掺入允许选择性地将 RNA 输送到 LSEC，同时最大限度地减少肝细胞对细胞的不需要的摄取。