The Extent to Which Lipid Nanoparticles Require Apolipoprotein E and Low-Density Lipoprotein Receptor for Delivery Changes with Ionizable Lipid Structure.
The Extent to Which Lipid Nanoparticles Require Apolipoprotein E and Low-Density Lipoprotein Receptor for Delivery Changes with Ionizable Lipid Structure.
复制标题
脂质纳米颗粒需要载脂蛋白 E 和低密度脂蛋白受体进行递送的程度随可电离脂质结构的变化而变化。
DOI：
10.1021/acs.nanolett.2c03741
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发表时间：
2022
期刊：
影响因子：
10.8
通讯作者：
Dahlman,JamesE
中科院分区：
文献类型：
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作者：
Paunovska,Kalina;DaSilvaSanchez,AlejandroJ;Lokugamage,MelissaP;Loughrey,David;Echeverri,ElisaSchrader;Cristian,Ana;Hatit,MarineZC;Santangelo,PhilipJ;Zhao,Kun;Dahlman,JamesE
脂质纳米粒(LNPs)已将治疗性RNA输送到人体肝细胞。载脂蛋白E(ApoE)在这些临床LNP-mRNA药物上的吸附已被证明有助于通过低密度脂蛋白受体(LDLR)进入肝细胞。由于载脂蛋白E-低密度脂蛋白受体在小鼠、非人类灵长类动物和人类中是保守的，这种机制的特征使临床过渡变得容易。最近，LNPs已经向小鼠和非人灵长类动物的非肝细胞传递了mRNA，这表明它们可以通过ApoE和LDLR非依赖的途径靶向新的细胞类型。为了验证这一假设，我们量化了60个LNPs如何在野生型小鼠和三个与脂质运输相关的敲除小鼠品系中传递具有细胞类型分辨率的mRNA：APOE-/-、LDLR-/-和PCSK9-/-。这些数据表明，基于二酮基哌嗪的脂类的疏水尾长可以被改变，以驱动体内ApoE和LDLR非依赖的递送。更广泛地说，这些结果支持这样的假设，即内源性LNP的转运可以通过改变脂质化学来调节。
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 deliveryin vivo. More broadly, the results support the hypothesis that endogenous LNP trafficking can be tuned by modifying lipid chemistry.