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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
Alexandros Papadimitriou
Annelie Angerfors
Alessandro Camponeschi
Manli Na
Mikko Hölttä
Pia Skantze
Svante Johansson
Martina Sundqvist
Johnny Lindquist
Tomas Kjellman
Inga-Lill Mårtensson
Tao Jin
Per Sunnerhagen
Sofia Östman
Lennart Lindfors
Hadi Valadi
Published in Nature Communications
Volume 10
Issue 1
ISSN 2041-1723
Publication year 2019
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Department of Chemistry and Molecular Biology
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.

Page Manager: Webmaster|Last update: 9/11/2012
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