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Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells

Journal article
Authors Maugeri Marco
Muhammad Nawaz
Hadi Valadi
Published in Nature Communications
Volume 10
ISSN 2041-1723
Publication year 2019
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Language en
Links https://doi.org/10.1038/s41467-019-...
Keywords Extracellular vesicles; Exosomes; mRNA therapy;
Subject categories Basic Medicine, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Abstract

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 ratios 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.

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