Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 09 2019
24 09 2019
Historique:
received:
13
09
2018
accepted:
23
08
2019
entrez:
26
9
2019
pubmed:
26
9
2019
medline:
14
1
2020
Statut:
epublish
Résumé
RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform for RNA delivery. However, the fate of the LNP-mRNA after endosome-engulfing and escape from the autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, for the first time, a link between LNP-mRNA endocytosis and its packaging into extracellular vesicles (endo-EVs: secreted after the endocytosis of LNP-mRNA). Endosomal escape of LNP-mRNA is dependent on the molar ratio between ionizable lipids and mRNA nucleotides. Our results show that fractions of ionizable lipids and mRNA (1:1 molar ratio of hEPO mRNA nucleotides:ionizable lipids) of endocytosed LNPs were detected in endo-EVs. Importantly, these EVs can protect the exogenous mRNA during in vivo delivery to produce human protein in mice, detected in plasma and organs. Compared to LNPs, endo-EVs cause lower expression of inflammatory cytokines.
Identifiants
pubmed: 31551417
doi: 10.1038/s41467-019-12275-6
pii: 10.1038/s41467-019-12275-6
pmc: PMC6760118
doi:
Substances chimiques
EPO protein, human
0
Lipids
0
RNA, Messenger
0
Erythropoietin
11096-26-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4333Références
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