N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice
Open accessAbstract
Messenger RNA as a therapeutic modality is becoming increasingly popular in the field of gene therapy. The realization that nucleobase modifications can greatly enhance the properties of mRNA by reducing the immunogenicity and increasing the stability of the RNA molecule (the Kariko paradigm) has been pivotal for this revolution. Here we find that mRNAs containing the N(1)-methylpseudouridine (m1Ψ) modification alone and/or in combination with 5-methylcytidine (m5C) outperformed the current state-of-the-art pseudouridine (Ψ) and/or m5C/Ψ-modified mRNA platform by providing up to ~44-fold (when comparing double modified mRNAs) or ~13-fold (when comparing single modified mRNAs) higher reporter gene expression upon transfection into cell lines or mice, respectively. We show that (m5C/)m1Ψ-modified mRNA resulted in reduced intracellular innate immunogenicity and improved cellular viability compared to (m5C/)Ψ-modified mRNA upon in vitro transfection. The enhanced capability of (m5C/)m1Ψ-modified mRNA to express proteins may at least partially be due to the increased ability of the mRNA to evade activation of endosomal Toll-like receptor 3 (TLR3) and downstream innate immune signaling. We believe that the (m5C/)m1Ψ-mRNA platform presented here may serve as a new standard in the field of modified mRNA-based therapeutics.
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Incorporation of naturally occurring nucleosides and stringent purification to remove double-stranded RNA contaminants can circumvent the high innate immunogenicity of purified unmodified IVT mRNA.
“This can be circumvented by the incorporation of naturally occurring nucleosides and by applying stringent purification to remove double-stranded RNA contaminants (19–21).”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [19]
1-methylpseudouridine (m1Ψ) has been demonstrated to reduce immunostimulation and increase protein expression.
“the Zika studies used mRNA harboring 1-methylpseudouridine (m1Ψ) which has been demonstrated to reduce immunostimulation and increase protein expression.26”
From Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines (2017) · cites this paper as [26]
Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS); additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.
“Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS). Additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.54,81,173–176”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [173]
Incorporating naturally occurring modified nucleotides into in vitro transcribed mRNA drastically reduces its innate immune activity.
“by incorporating naturally occurring modified nucleotides into the IVT mRNA, its innate immune activity could be drastically reduced [6,7]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [6]
Modified and purified in vitro transcribed mRNA enables much higher protein expression and has a more favorable safety profile, drastically reducing production of pro-inflammatory type I interferons.
“modified and purified IVT mRNA enables much higher protein expression and has a more favorable safety profile, as it drastically reduces the production of pro-inflammatory type I IFNs [6]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [6]
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Kairuz, D., Samudh, N., Ely, A., Arbuthnot, P., & Bloom, K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1018961 · Cited by 25 · see citing works
mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice
Liu-Chen, S., Connolly, B., Cheng, L., Subramanian, R. R., & Han, Z. (2018) · Scientific Reports · doi:10.1038/s41598-018-26298-4 · Cited by 20 · see citing works
- Authors
- Andries, O., Mc Cafferty, S., De Smedt, S. C., Weiss, R., Sanders, N. N., & Kitada, T.
- Affiliations
- Ghent University (BE)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Sanders, Niek N.
- Kitada, Tasuku
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 217
- Pages
- 337-344
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W1215958058
- Cited by
- 701
- References
- 36
- Citations by year
- 2026: 96 · 2025: 123 · 2024: 123 · 2023: 107 · 2022: 91 · 2021: 62 · 2020: 29 · 2019: 24 · 2018: 24 · 2017: 14 · 2016: 6 · 2015: 2
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- green
- biblio.ugent.be
- Licence
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Funders
- Defense Advanced Research Projects Agency
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- N1-methylpseudouridine, pseudouridine, 5-methylcytidine, mRNA modification, mRNA therapeutics, protein expression, immunogenicity, TLR3, endosomal escape, innate immune signaling, reporter gene expression, mRNA stability
- MeSH terms
- Animals, Cell Line, Cell Survival, Cytidine, Humans, Mice, Inbred BALB C, Pseudouridine, RNA, Messenger, Transfection, Cell Line, Tumor, Luciferases, Firefly
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