Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia 30332, United States.
Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
Nano Lett. 2022 Dec 28;22(24):10025-10033. doi: 10.1021/acs.nanolett.2c03741. Epub 2022 Dec 15.
Lipid nanoparticles (LNPs) have delivered therapeutic RNA to hepatocytes in humans. Adsorption of apolipoprotein E (ApoE) onto these clinical LNP-mRNA drugs has been shown to facilitate hepatocyte entry via the low-density lipoprotein receptor (LDLR). Since ApoE-LDLR trafficking is conserved in mice, non-human primates, and humans, characterizing this mechanism eased clinical transition. Recently, LNPs have delivered mRNA to non-hepatocytes in mice and non-human primates, suggesting they can target new cell types via ApoE- and LDLR-independent pathways. To test this hypothesis, we quantified how 60 LNPs delivered mRNA with cell type resolution in wild-type mice and three knockout mouse strains related to lipid trafficking: ApoE, LDLR, and PCSK9. These data suggest that the hydrophobic tail length of diketopiperazine-based lipids can be changed to drive ApoE- and LDLR-independent delivery . More broadly, the results support the hypothesis that endogenous LNP trafficking can be tuned by modifying lipid chemistry.
脂质纳米颗粒 (LNPs) 已将治疗性 RNA 递送至人体肝细胞。在这些临床 LNPs-mRNA 药物上吸附载脂蛋白 E (ApoE) 已被证明可通过低密度脂蛋白受体 (LDLR) 促进肝细胞进入。由于 ApoE-LDLR 转运在小鼠、非人类灵长类动物和人类中是保守的，因此表征这种机制有助于临床转化。最近，LNPs 已将 mRNA 递送至小鼠和非人类灵长类动物的非肝细胞中，这表明它们可以通过 ApoE 和 LDLR 非依赖性途径靶向新的细胞类型。为了验证这一假设，我们定量分析了 60 个 LNPs 在野生型小鼠和三种与脂质转运相关的基因敲除小鼠品系（ApoE、LDLR 和 PCSK9）中如何以细胞类型分辨率递送 mRNA。这些数据表明，基于二酮哌嗪的脂质的疏水性尾部长度可以改变以驱动 ApoE 和 LDLR 非依赖性递药。更广泛地说，这些结果支持了通过修饰脂质化学可以调节内源性 LNP 转运的假设。
