内体
信使核糖核酸
磷脂
化学
核酸
核糖核酸
细胞生物学
脂质体
体内
生物化学
生物
膜
基因
细胞
遗传学
作者
Ester Alvarez Benedicto,Lukas Farbiak,Martha Marquez Ramirez,Xu Wang,Lindsay T. Johnson,Osamah Mian,Erick Damian Guerrero,Daniel J. Siegwart
出处
期刊:Biomaterials Science
[The Royal Society of Chemistry]
日期:2022-01-01
卷期号:10 (2): 549-559
被引量:32
摘要
Lipid nanoparticles (LNPs) have been established as an essential platform for nucleic acid delivery. Efforts have led to the development of vaccines that protect against SARS-CoV-2 infection using LNPs to deliver messenger RNA (mRNA) coding for the viral spike protein. Out of the four essential components that comprise LNPs, phospholipids represent an underappreciated opportunity for fundamental and translational study. We investigated this avenue by systematically modulating the identity of the phospholipid in LNPs with the goal of identifying specific moieties that directly enhance or hinder delivery efficacy. Results indicate that phospholipid chemistry can enhance mRNA delivery by increasing membrane fusion and enhancing endosomal escape. Phospholipids containing phosphoethanolamine (PE) head groups likely increase endosomal escape due to their fusogenic properties. Additionally, it was found that zwitterionic phospholipids mainly aided liver delivery, whereas negatively charged phospholipids changed the tropism of the LNPs from liver to spleen. These results demonstrate that the choice of phospholipid plays a role intracellularly by enhancing endosomal escape, while also driving organ tropism in vivo. These findings were then applied to Selective Organ Targeting (SORT) LNPs to manipulate and control spleen-specific delivery. Overall, selection of the phospholipid in LNPs provides an important handle to design and optimize LNPs for improved mRNA delivery and more effective therapeutics.
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