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Mild Innate Immune Activation Overrides Efficient Nanoparticle‐Mediated RNA Delivery
Open accessAbstract
Clinical mRNA delivery remains challenging, in large part because how physiology alters delivery in vivo remains underexplored. For example, mRNA delivered by lipid nanoparticles (LNPs) is being considered to treat inflammation, but whether inflammation itself changes delivery remains understudied. Relationships between immunity, endocytosis, and mRNA translation lead to hypothesize that toll‐like receptor 4 (TLR4) activation reduced LNP‐mediated mRNA delivery. Therefore, LNP uptake, endosomal escape, and mRNA translation with and without TLR4 activation are quantified. In vivo DNA barcoding is used to discover a novel LNP that delivers mRNA to Kupffer cells at clinical doses; unlike most LNPs, this LNP does not preferentially target hepatocytes. TLR4 activation blocks mRNA translation in all tested cell types, without reducing LNP uptake; inhibiting TLR4 or its downstream effector protein kinase R improved delivery. The discrepant effects of TLR4 on i) LNP uptake and ii) translation suggests TLR4 activation can “override” LNP targeting, even after mRNA is delivered into target cells. Given near‐future clinical trials using mRNA to modulate inflammation, this highlights the need to understand inflammatory signaling in on‐ and off‐target cells. More generally, this suggests an LNP which delivers mRNA to one inflammatory disease may not deliver mRNA to another.
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“Nevertheless, immune responses to IVT mRNA may also suppress antigen expression and negatively affect vaccine efficacy175,180,181.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [175]
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“Although the immunogenicity of these lipids has not yet been fully understood, complement system and Toll-like receptors may participate in innate immune activation170,173–175.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [175]
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Metadata
- Authors
- Lokugamage, M. P., Gan, Z., Zurla, C., Levin, J., Islam, F. Z., Kalathoor, S., Sato, M., Sago, C. D., Santangelo, P. J., & Dahlman, J. E.
- Affiliations
- Georgia Institute of Technology (US)
- Corresponding author
- Dahlman, James E.
- ORCID
- Venue
- Advanced Materials
- Publisher
- Wiley
- Published
- 2019-11-19
- Volume
- 32
- Issue
- 1
- Pages
- e1904905-e1904905
- ISSN
- 0935-9648 (ISSN-L)
- 1521-4095
- PMC
- PMC7029413
- OpenAlex
- W2990482336
- Cited by
- 126
- References
- 63
- Citations by year
- 2026: 18 · 2025: 12 · 2024: 16 · 2023: 27 · 2022: 29 · 2021: 12 · 2020: 11
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Advanced Materials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Parkinson's Disease Foundation (PDF‐JFA‐1860)
- 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 › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- lipid nanoparticles, mRNA delivery, TLR4, innate immune activation, inflammation, Kupffer cells, endosomal escape, mRNA translation, PKR, endocytosis
- MeSH terms
- RAW 264.7 Cells, Animals, Endocytosis, Immunity, Innate, Lipids, Lipopolysaccharides, Macrophages, Mice, Transgenic, Endosomes, RNA, Messenger, Toll-Like Receptor 4, Mice, Nanoparticles
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