先天免疫系统
TLR4型
翻译(生物学)
内体
信使核糖核酸
效应器
炎症
免疫系统
体内
内吞作用
细胞生物学
受体
生物
免疫学
生物化学
细胞内
遗传学
基因
作者
Melissa P. Lokugamage,Zubao Gan,Chiara Zurla,Joel Levin,Fatima Z. Islam,Sujay Kalathoor,Manaka Sato,Cory D. Sago,Philip J. Santangelo,James E. Dahlman
标识
DOI:10.1002/adma.201904905
摘要
Clinical mRNA delivery remains challenging, in large part because how physiology alters delivery in vivo remains underexplored. For example, mRNA delivered by lipid nanoparticles (LNPs) is being considered to treat inflammation, but whether inflammation itself changes delivery remains understudied. Relationships between immunity, endocytosis, and mRNA translation lead to hypothesize that toll-like receptor 4 (TLR4) activation reduced LNP-mediated mRNA delivery. Therefore, LNP uptake, endosomal escape, and mRNA translation with and without TLR4 activation are quantified. In vivo DNA barcoding is used to discover a novel LNP that delivers mRNA to Kupffer cells at clinical doses; unlike most LNPs, this LNP does not preferentially target hepatocytes. TLR4 activation blocks mRNA translation in all tested cell types, without reducing LNP uptake; inhibiting TLR4 or its downstream effector protein kinase R improved delivery. The discrepant effects of TLR4 on i) LNP uptake and ii) translation suggests TLR4 activation can "override" LNP targeting, even after mRNA is delivered into target cells. Given near-future clinical trials using mRNA to modulate inflammation, this highlights the need to understand inflammatory signaling in on- and off-target cells. More generally, this suggests an LNP which delivers mRNA to one inflammatory disease may not deliver mRNA to another.
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