Selection of UTRs in mRNA-Based Gene Therapy and Vaccines
Abstract
The untranslated regions (UTRs) of messenger RNAs (mRNAs) play a crucial role in regulating translational efficiency, stability, and tissue-specific expression. The review describes various applications and challenges of UTR design in the development of gene therapy and mRNA-based therapeutics. UTRs affect critical biological functions, such as mRNA stability, modulation of protein synthesis, and attenuation of immune response. Incorporating tissue-specific microRNA (miRNA)-binding sites into 3' UTRs might improve precise targeting of transgene expression and minimize off-target effects. Nucleotide modifications (pseudouridine, N1-methyladenosine, and N4-acetylcytidine) in mRNA and UTRs in particular, improve mRNA stability and translational efficiency. At the same time, several challenges remain, such as lack of consensus on UTRs best suited for certain biomedical applications. Current efforts are focused on integrating high-throughput screening, computational modeling, and experimental validation to refine UTR-based therapeutic strategies. The review presents current information on the design of UTRs and their role in therapeutic applications, with special focus on the possibilities and limitations of existing approaches.
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Inclusion of specific untranslated regions is a promising strategy to enhance stability and efficacy of mRNA therapeutics.
“Recent studies demonstrate that, in addition to the incorporation of modified nucleosides, the inclusion of specific untranslated regions represents a highly promising strategy to enhance the stability and efficacy of mRNA therapeutics [12][13][14][15][16].”
From Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity (2026) · cites this paper as [14]
Several synthetic 5′ UTR sequences have demonstrated strong performance.
“However, several synthetic sequences have also demonstrated strong performance [14,19].”
From Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity (2026) · cites this paper as [14]
The 5′ UTR may contain additional regulatory elements such as uAUGs, uORFs, G-quadruplexes, 5′ TOP, and recognition sites for RNA-binding proteins and small RNAs that modulate translation rates.
“The 5′ UTR may also contain additional regulatory elements, such as upstream AUG codons (uAUGs) and upstream open reading frames (uORFs), G-quadruplexes, a terminal oligopyrimidine tract (5′ TOP), and recognition sites for RNA-binding proteins and small RNAs that modulate translation rates [14].”
From Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity (2026) · cites this paper as [14]
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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
- Volkhin, I. A., Paremskaia, A. I., Dashian, M. A., Smeshnova, D. S., Pavlov, R. E., Mityaeva, O. N., Volchkov, P. Y., & Deviatkin, A. A.
- Affiliations
- Lomonosov Moscow State University (RU)
- Pirogov Russian National Research Medical University (RU)
- Centre of Advanced Studies (RU)
- Moscow Clinical Scientific Center (RU)
- The Federal State Budgetary Scientific Institution "Izmerov Research Institute of Occupational Health" (RU)
- Corresponding author
- Deviatkin, Andrei A.
- ORCID
- Venue
- Biochemistry (Moscow)
- Publisher
- Pleiades Publishing Ltd
- Published
- 2025-06
- Volume
- 90
- Issue
- 6
- Pages
- 725-753
- ISSN
- 0006-2979 (ISSN-L)
- 1608-3040
- OpenAlex
- W4411932235
- Cited by
- 7
- References
- 23
- Citations by year
- 2026: 5 · 2025: 2
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemistry (Moscow) (publishedVersion)
- PubMed (publishedVersion)
- 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
- untranslated regions, mRNA vaccines, microRNA binding sites, tissue-specific gene expression, mRNA stability, translation efficiency, nucleoside modification, pseudouridine, N1-methyladenosine, N4-acetylcytidine, off-target effects, high-throughput screening, computational modeling
- MeSH terms
- Animals, Humans, RNA, Messenger, Vaccines, Genetic Therapy, Untranslated Regions, MicroRNAs
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