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Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing
Nature Materials ( IF 41.2 ) Pub Date : 2021-02-04 , DOI: 10.1038/s41563-020-00886-0
Shuai Liu 1 , Qiang Cheng 1 , Tuo Wei 1 , Xueliang Yu 1 , Lindsay T Johnson 1 , Lukas Farbiak 1 , Daniel J Siegwart 1
Affiliation  

Endosomal escape remains a fundamental barrier hindering the advancement of nucleic acid therapeutics. Taking inspiration from natural phospholipids that comprise biological membranes, we report the combinatorial synthesis of multi-tailed ionizable phospholipids (iPhos) capable of delivering messenger RNA or mRNA/single-guide RNA for gene editing in vivo. Optimized iPhos lipids are composed of one pH-switchable zwitterion and three hydrophobic tails, which adopt a cone shape in endosomal acidic environments to facilitate membrane hexagonal transformation and subsequent cargo release from endosomes. Structure–activity relationships reveal that iPhos chemical structure can control in vivo efficacy and organ selectivity. iPhos lipids synergistically function with various helper lipids to formulate multi-component lipid nanoparticles (called iPLNPs) for selective organ targeting. Zwitterionic, ionizable cationic and permanently cationic helper lipids enable tissue-selective mRNA delivery and CRISPR–Cas9 gene editing in spleen, liver and lungs (respectively) following intravenous administration. This rational design of functional phospholipids demonstrates substantial value for gene editing research and therapeutic applications.



中文翻译:

用于器官选择性 mRNA 递送和 CRISPR–Cas 基因编辑的膜去稳定化可电离磷脂

内体逃逸仍然是阻碍核酸疗法进步的基本障碍。从构成生物膜的天然磷脂中汲取灵感,我们报告了多尾可电离磷脂 (iPhos) 的组合合成,该磷脂能够递送信使 RNA 或 mRNA/单向导 RNA 用于体内基因编辑。优化的 iPhos 脂质由一个 pH 可切换的两性离子和三个疏水尾部组成,它们在内体酸性环境中呈锥形,以促进膜六角形转化和随后的内体货物释放。构效关系表明 iPhos 化学结构可以控制体内功效和器官选择性。iPhos 脂质与各种辅助脂质协同作用,以配制用于选择性器官靶向的多组分脂质纳米颗粒(称为 iPLNP)。两性离子、可电离阳离子和永久阳离子辅助脂质能够在静脉内给药后在脾脏、肝脏和肺(分别)中进行组织选择性 mRNA 递送和 CRISPR-Cas9 基因编辑。这种功能性磷脂的合理设计对基因编辑研究和治疗应用具有重要价值。

更新日期:2021-02-04
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