Expression Kinetics and Innate Immune Response after Electroporation and LNP-Mediated Delivery of a Self-Amplifying mRNA in the Skin
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Abstract
In this work, we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid-nanoparticle (LNP)-mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression, with the plateau between day 3 and day 10. The overall protein expression of sa-RNA was significantly higher than that obtained after electroporation of plasmid DNA (pDNA) or non-replication mRNAs. Moreover, using IFN-β reporter mice, we elucidated that intradermal electroporation of sa-RNA induced a short-lived moderate innate immune response, which did not affect the expression of the sa-RNA. A completely different expression profile and innate immune response were observed when LNPs were used. The expression peaked 24 h after intradermal injection of sa-RNA-LNPs and subsequently showed a sharp drop. This drop might be explained by a translational blockage caused by the strong innate immune response that we observed in IFN-β reporter mice shortly (4 h) after intradermal injection of sa-RNA-LNPs. A final interesting observation was the capacity of sa-RNA-LNPs to transfect the draining lymph nodes after intradermal injection.
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The early and intense type I IFN response induced by saRNA detection hinders replication and antigen expression.
“The early and intense type I IFN response induced by saRNA detection hinders replication and antigen expression, similar to unmodified mRNA5,13–15.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [15]
The Results report an early, stronger IFN-β response after LNP delivery of saRNA, and the Discussion links that response to reduced reporter-protein expression. But the paper presents the expression mechanism as a likely translation blockage, not a demonstrated inhibition of replication or antigen expression; it also says the weaker response after electroporation likely did not reduce expression. Page numbers are unavailable in our copy. (LLM, conf=0.86)
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References 59 · Cited by 83
- Authors
- Huysmans, H., Zhong, Z., De Temmerman, J., Mui, B. L., Tam, Y. K., Mc Cafferty, S., Gitsels, A., Vanrompay, D., & Sanders, N. N.
- Affiliations
- Ghent University (BE)
- Acuitas Therapeutics (Canada) (CA)
- Corresponding author
- Sanders, Niek N.
- Venue
- Molecular Therapy - Nucleic Acids
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 17
- Pages
- 867-878
- ISSN
- 2162-2531 (ISSN-L)
- PMC
- PMC6722285
- OpenAlex
- W2966702973
- Cited by
- 83
- References
- 59
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 16 · 2023: 8 · 2022: 11 · 2021: 11 · 2020: 7 · 2019: 1
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ghent University (BOF15/GOA/013)
- China Scholarship Council (201607650018)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Keywords
- self-amplifying mRNA, electroporation, lipid nanoparticles, intradermal injection, expression kinetics, innate immune response, mRNA vaccines
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