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Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
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...
| Autores principales: | , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group UK
2019
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760118/ https://www.ncbi.nlm.nih.gov/pubmed/31551417 http://dx.doi.org/10.1038/s41467-019-12275-6 |
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| author | Maugeri, Marco Nawaz, Muhammad Papadimitriou, Alexandros Angerfors, Annelie Camponeschi, Alessandro Na, Manli Hölttä, Mikko Skantze, Pia Johansson, Svante Sundqvist, Martina Lindquist, Johnny Kjellman, Tomas Mårtensson, Inga-Lill Jin, Tao Sunnerhagen, Per Östman, Sofia Lindfors, Lennart Valadi, Hadi |
| author_facet | Maugeri, Marco Nawaz, Muhammad Papadimitriou, Alexandros Angerfors, Annelie Camponeschi, Alessandro Na, Manli Hölttä, Mikko Skantze, Pia Johansson, Svante Sundqvist, Martina Lindquist, Johnny Kjellman, Tomas Mårtensson, Inga-Lill Jin, Tao Sunnerhagen, Per Östman, Sofia Lindfors, Lennart Valadi, Hadi |
| author_sort | Maugeri, Marco |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-6760118 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2019 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-67601182019-09-26 Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells Maugeri, Marco Nawaz, Muhammad Papadimitriou, Alexandros Angerfors, Annelie Camponeschi, Alessandro Na, Manli Hölttä, Mikko Skantze, Pia Johansson, Svante Sundqvist, Martina Lindquist, Johnny Kjellman, Tomas Mårtensson, Inga-Lill Jin, Tao Sunnerhagen, Per Östman, Sofia Lindfors, Lennart Valadi, Hadi Nat Commun Article 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. Nature Publishing Group UK 2019-09-24 /pmc/articles/PMC6760118/ /pubmed/31551417 http://dx.doi.org/10.1038/s41467-019-12275-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| spellingShingle | Article Maugeri, Marco Nawaz, Muhammad Papadimitriou, Alexandros Angerfors, Annelie Camponeschi, Alessandro Na, Manli Hölttä, Mikko Skantze, Pia Johansson, Svante Sundqvist, Martina Lindquist, Johnny Kjellman, Tomas Mårtensson, Inga-Lill Jin, Tao Sunnerhagen, Per Östman, Sofia Lindfors, Lennart Valadi, Hadi Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells |
| title | Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells |
| title_full | Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells |
| title_fullStr | Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells |
| title_full_unstemmed | Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells |
| title_short | Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells |
| title_sort | linkage between endosomal escape of lnp-mrna and loading into evs for transport to other cells |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760118/ https://www.ncbi.nlm.nih.gov/pubmed/31551417 http://dx.doi.org/10.1038/s41467-019-12275-6 |
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