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Incorporation of Pseudouridine Into mRNA Yields Superior Nonimmunogenic Vector With Increased Translational Capacity and Biological Stability
Open accessAbstract
In vitro-transcribed mRNAs encoding physiologically important proteins have considerable potential for therapeutic applications. However, in its present form, mRNA is unfeasible for clinical use because of its labile and immunogenic nature. Here, we investigated whether incorporation of naturally modified nucleotides into transcripts would confer enhanced biological properties to mRNA. We found that mRNAs containing pseudouridines have a higher translational capacity than unmodified mRNAs when tested in mammalian cells and lysates or administered intravenously into mice at 0.015-0.15 mg/kg doses. The delivered mRNA and the encoded protein could be detected in the spleen at 1, 4, and 24 hours after the injection, where both products were at significantly higher levels when pseudouridine-containing mRNA was administered. Even at higher doses, only the unmodified mRNA was immunogenic, inducing high serum levels of interferon-alpha (IFN-alpha). These findings indicate that nucleoside modification is an effective approach to enhance stability and translational capacity of mRNA while diminishing its immunogenicity in vivo. Improved properties conferred by pseudouridine make such mRNA a promising tool for both gene replacement and vaccination.
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“Both of the candidates are pharmacologically optimized 15,16 , N 1 -methylpseudouridine nucleoside-modified mRNAs 17 that are administered intramuscularly in a prime-boost regimen 21”
From BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans (2021) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“which is widely believed to be critical to the recent success of mRNA vaccines1,2,10,37,38”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [38]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein.”
From Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine (2020) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Substitution of chemically modified nucleotides in messenger ribonucleic acid (mRNA) enhances stability and transfection capability, and decreases immunogenicity1–3”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [20]
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“Karikó et al. reported that mRNA with nucleoside modifications were insensitive to ribonuclease L (RNase L) degradation, did not activate TLRs and protein kinase R, which subsequently resulted in improved translational efficiency and stability, compared to unmodified mRNA (20).”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Substitution of uridine with m1Ψ in mRNA significantly improves the translation efficiency and decreases innate immunogenicity (20).”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [20]
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In the citing paper
“For instance, a successful approach to avoid overactivation of the innate immunity and increase translation of mRNA is the use of modified nucleosides such as methyl-pseudo uridine.29”
From Combining an optimized mRNA template with a double purification process allows strong expression of in vitro transcribed mRNA (2021) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“The two uridine analogs pseudouridine (Ψ) or 1-methyl-pseudouridine (m1Ψ) are widely used for mRNA therapeutics because they can increase mRNA stability and help modulate the host immune response31,32.”
From Human 5′ UTR design and variant effect prediction from a massively parallel translation assay (2019) · cites this paper as [31]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“In particular, we focused on ψ and m1ψ, since these substitutions for U have been widely adopted for mRNA therapeutics and vaccines due to improved in-cell translation and to better control of innate immune responses2,3,8,67 through avoidance of recognition by cellular toll-like receptors (TLR7 and TLR8)68, RIG‑I, and PKR69–71.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [69]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Replacing of uridine by pseudouridine into mRNA gives superior nonimmunogenic mRNA with increased translational capacity and biological stability (20).”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [20]
The cited source says what the claim attributes to it.
In the citing paper
“Our work principally confirms that conventional unmodified mRNAs are inferior to molecules harboring specific nucleoside modifications as suggested by various recent reports,23,24,25,26,27 however, the picture changes dramatically with a sophisticated sequence-engineering.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [23]
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In the citing paper
“Although pseudouridine is primarily found in tRNA, rRNA, and small nuclear RNAs, pseudouridine-containing mRNAs were still translated and produced even more protein compared to unmodified mRNA.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [23]
The cited source says what the claim attributes to it.
In the citing paper
“As mammalian host cells attack unmodified exogeneous RNA [12,13], all U nucleotides were replaced by N1-methylpseudouridine (Ψ) [14,15].”
From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [12]
In the citing paper
“To avoid this, Karikó and colleagues found that adding modified nucleosides during IVT of mRNA can significantly reduce the host inflammatory response without affecting protein expression.81,159”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [159]
In the citing paper
“Studies have found that replacing original nucleosides with m6A and s2U inhibits activation of TLR3, whereas activation of TLR7 and TLR8 is blocked when using ψ, 5-methyluridine (m5U), m6A, and s2U, thereby inhibiting the innate immune responses and improving protein translation efficiency.81,159,171”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [159]
In the citing paper
“However, the incorporation of modified nucleosides into mRNA can significantly improve the biological stability and translational capacity of the mRNA while decreasing the innate immune response.36, 37, 38”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [37]
In the citing paper
“These alterations possibly lead to a blunted specific immune response.37,133, 134, 135”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [37]
In the citing paper
“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 [180]
In the citing paper
“Taken together, these findings resulted in a paradigm of the design of mRNA formulations for vaccination.One strategy is to use mRNA which is fully optimized to obtain a strong adjuvant effect, another is to work with 'modified' mRNA with high translation capacity, and thus improved antigen bio-availability [43,62].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [43]
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Metadata
- Authors
- Karikó, K., Muramatsu, H., Welsh, F. A., Ludwig, J., Kato, H., Akira, S., & Weissman, D.
- Affiliations
- University of Pennsylvania (US)
- Rockefeller University (US)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Karikó, Katalin
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 16
- Issue
- 11
- Pages
- 1833-1840
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC2775451
- OpenAlex
- W2058647478
- Cited by
- 1,930
- References
- 30
- Citations by year
- 2026: 249 · 2025: 304 · 2024: 279 · 2023: 249 · 2022: 233 · 2021: 227 · 2020: 97 · 2019: 57 · 2018: 58 · 2017: 40 · 2016: 39 · 2015: 37 · 2014: 17 · 2013: 22 · 2012: 11
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- University of California, Riverside
- National Heart, Lung, and Blood Institute (R42HL087688, HL87688)
- National Institute of Allergy and Infectious Diseases (R01AI050484, AI050484)
- National Institute of Neurological Disorders and Stroke (NS29331, R01NS029331)
- 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
- pseudouridine, mRNA modification, nucleoside modification, in vitro transcribed mRNA, interferon-alpha, mRNA stability, translational capacity, mRNA vaccines, gene replacement therapy, intravenous delivery
- MeSH terms
- Animals, Cell Line, Genetic Vectors, Humans, Luciferases, Pseudouridine, RNA, Messenger, Transcription, Genetic, Protein Biosynthesis, Mice
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