Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States.
Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States.
Nano Lett. 2020 Jul 8;20(7):5167-5175. doi: 10.1021/acs.nanolett.0c00596. Epub 2020 Jun 9.
The clinical translation of messengerRNA (mRNA) drugs has been slowed by a shortage of delivery vehicles that potently and safely shuttle mRNA into target cells. Here, we describe the properties of a particularly potent branched-tail lipid nanoparticle that delivers mRNA to >80% of three major liver cell types. We characterize mRNA delivery spatially, temporally, and as a function of injection type. Following intravenous delivery, our lipid nanoparticle induced greater protein expression than two benchmark lipids, C12-200 and DLin-MC3-DMA, at an mRNA dose of 0.5 mg/kg. Lipid nanoparticles were sufficiently potent to codeliver three distinct mRNAs (firefly luciferase, mCherry, and erythropoietin) and, separately, Cas9 mRNA and single guide RNA (sgRNA) for proof-of-concept nonviral gene editing in mice. Furthermore, our branched-tail lipid nanoparticle was neither immunogenic nor toxic to the liver. Together, these results demonstrate the unique potential of this lipid material to improve the management of diseases rooted in liver dysfunction.
信使 RNA（mRNA）药物的临床转化受到递药载体的限制，这些载体能够有效地将 mRNA 安全递送至靶细胞。在这里，我们描述了一种具有特殊效力的分支状尾部脂质纳米颗粒的特性，该颗粒能将 mRNA 递送至>80%的三种主要的肝实质细胞。我们从空间、时间和注射类型等方面对 mRNA 的递送来进行了表征。静脉注射后，与两种基准脂质 C12-200 和 DLin-MC3-DMA 相比，我们的脂质纳米颗粒在 0.5mg/kg 的 mRNA 剂量下诱导了更高的蛋白表达。脂质纳米颗粒的效力足以共递三种不同的 mRNA（萤火虫荧光素酶、mCherry 和促红细胞生成素），并分别递 Cas9 mRNA 和单指导 RNA（sgRNA），以在小鼠中进行概念验证的非病毒基因编辑。此外，我们的分支状尾部脂质纳米颗粒既没有免疫原性，也没有对肝脏造成毒性。综上所述，这些结果表明了这种脂质材料在改善以肝功能障碍为根源的疾病的治疗方面具有独特的潜力。
