RNA stability enhancers for durable base-modified mRNA therapeutics
Open accessAbstract
The limited stability of mRNA in vivo remains a major challenge for vaccines and therapeutics. While alternative RNA formats such as circular RNA or self-amplifying RNA offer greater durability, these modalities often suffer from low translation, modification incompatibility and difficult manufacturing. To overcome these limitations, we screen 196,277 viral sequences and identify eleven elements that strongly enhance mRNA stability and translation. Mechanistically, they recruit TENT4 to extend the poly(A) tail, preventing deadenylation. Five of them are compatible with N 1 -methylpseudouridine, which improves mRNA efficacy and reduces immunogenicity. An element named A7 demonstrates particularly robust performance across cell types, delivery methods, modifications and coding sequences, making linear mRNA as stable as circular RNA while achieving higher translation efficiency. In mouse liver, A7-containing linear mRNA exhibits substantially higher protein levels than circular RNA, with sustained expression lasting for over 2 weeks. These RNA stability enhancers enable robust linear mRNA platforms that combine high and durable expression, low immunogenicity and simple manufacturing.
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The 5′ UTRs of highly expressed natural genes such as HBA1 and HBB provide high translational activity and mRNA stability.
“These criteria are met by the 5′ UTRs of highly expressed natural genes such as HBA1 and HBB, encoding α-and β-globin, respectively, which provide high translational activity and mRNA stability [21,22].”
From Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity (2026) · cites this paper as [22]
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Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity
Mazunina, E. P., Dzharullaeva, A. S., Kleymenov, D. A., Bykonia, E. N., Kozlova, S. R., Usachev, E. V., Panova, E. A., Konopleva, M. V., Telegina, D. V., Kukushkina-Zvezdova, A. A., et al. (2026) · Scientific Reports · doi:10.1038/s41598-026-59586-5
- Authors
- Jung, S.-J., Seo, J. J., Lee, S., Hyun, S.-I., Lee, J.-E., Lee, S., Lee, Y., Chang, H., Lee, H., Kim, J.-H., & Kim, V. N.
- Affiliations
- Seoul National University (KR)
- Harvard University (US)
- Corresponding author
- Kim, V. Narry
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2025-11-07
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W4415988384
- Cited by
- 26
- References
- 16
- Citations by year
- 2026: 24 · 2025: 2
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (cc-by)
- Funders
- Seoul National University (5200-20250001)
- 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 Research and Splicing
- Keywords
- mRNA stability, N1-methylpseudouridine, deadenylation, circular RNA, self-amplifying RNA, translation efficiency, immunogenicity, mRNA vaccines, mRNA therapeutics, liver expression
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