Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
Open accessAbstract
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.
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LNPs stimulated massive infiltration of monocytes and macrophages, which functioned as adjuvants.
“and LNPs also stimulated massive infiltration of monocytes and macrophages, which functioned as adjuvants, as described previously (Maugeri et al., 2019).”
From A thermostable mRNA vaccine against COVID-19 (2020) · cites this paper as Maugeri et al., 2019
The Results section, “Expression of inflammatory cytokines against systemic delivery of EVs and LNPs” (page not provided), reports that injected LNPs elicited inflammatory cytokines in mice. It does not report massive infiltration of monocytes or macrophages, or show that those cells functioned as adjuvants. (LLM, conf=0.86)
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- Authors
- Maugeri, M., Nawaz, M., Papadimitriou, A., Angerfors, A., Camponeschi, A., Na, M., Hölttä, M., Skantze, P., Johansson, S., Sundqvist, M., Lindquist, J., Kjellman, T., Mårtensson, I.-L., Jin, T., Sunnerhagen, P., Östman, S., Lindfors, L., & Valadi, H.
- Affiliations
- University of Gothenburg (SE)
- AstraZeneca (Sweden) (SE)
- Corresponding author
- Valadi, Hadi
- ORCID
- Venue
- Nature Communications
- Published
- 2019-09-24
- Volume
- 10
- Issue
- 1
- Pages
- 4333-4333
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6760118
- OpenAlex
- W2975259971
- Cited by
- 428
- References
- 62
- Citations by year
- 2026: 50 · 2025: 79 · 2024: 76 · 2023: 75 · 2022: 77 · 2021: 45 · 2020: 21 · 2019: 2 · 2018: 1
- FWCI
- 11.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Vetenskapsrådet
- VINNOVA (2017-02960)
- Stiftelsen för Strategisk Forskning (IRC15-0065)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- lipid nanoparticles, mRNA delivery, endosomal escape, extracellular vesicles, endocytosis, ionizable lipids, erythropoietin, autophagy-lysosome pathway, in vivo delivery, inflammatory cytokines, RNA therapeutics
- MeSH terms
- Extracellular Vesicles, Animals, Biological Transport, Cell Line, Cytoplasm, Erythropoietin, Female, Humans, Lipids, Mice, Inbred C57BL, Endosomes, RNA, Messenger, Lipid Metabolism, Mice, Nanoparticles
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