Theoretical basis for stabilizing messenger RNA through secondary structure design
Open accessPublished version of a preprint
Abstract
RNA hydrolysis presents problems in manufacturing, long-term storage, world-wide delivery and in vivo stability of messenger RNA (mRNA)-based vaccines and therapeutics. A largely unexplored strategy to reduce mRNA hydrolysis is to redesign RNAs to form double-stranded regions, which are protected from in-line cleavage and enzymatic degradation, while coding for the same proteins. The amount of stabilization that this strategy can deliver and the most effective algorithmic approach to achieve stabilization remain poorly understood. Here, we present simple calculations for estimating RNA stability against hydrolysis, and a model that links the average unpaired probability of an mRNA, or AUP, to its overall hydrolysis rate. To characterize the stabilization achievable through structure design, we compare AUP optimization by conventional mRNA design methods to results from more computationally sophisticated algorithms and crowdsourcing through the OpenVaccine challenge on the Eterna platform. We find that rational design on Eterna and the more sophisticated algorithms lead to constructs with low AUP, which we term ‘superfolder’ mRNAs. These designs exhibit a wide diversity of sequence and structure features that may be desirable for translation, biophysical size, and immunogenicity. Furthermore, their folding is robust to temperature, computer modeling method, choice of flanking untranslated regions, and changes in target protein sequence, as illustrated by rapid redesign of superfolder mRNAs for B.1.351, P.1 and B.1.1.7 variants of the prefusion-stabilized SARS-CoV-2 spike protein. Increases in in vitro mRNA half-life by at least two-fold appear immediately achievable.
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gE mRNA molecules were more stable than spike mRNAs owing to their shorter length.
“We also observed that gE mRNA molecules were more stable than spike mRNAs owing to their shorter length34.”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [34]
The Introduction (page unavailable) predicts that longer mRNAs are more susceptible to hydrolysis, supporting shorter length as a possible reason for greater stability. The paper does not report a gE-versus-spike mRNA comparison or establish that length caused the citing authors’ observed difference. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPERSIST-seq data across different CDS types confirmed the effect of CDS length on RNA stability.
“The strongest prediction of previous theoretical modeling7 was that length changes should drive the most variation in in-solution stability, and PERSIST-seq data across different different CDS types confirmed the effect of CDS length on RNA stability, (Fig. 2G).”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [7]
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- Authors
- Wayment-Steele, H. K., Kim, D. S., Choe, C. A., Nicol, J. J., Wellington-Oguri, R., Watkins, A. M., Parra Sperberg, R. A., Huang, P.-S., Participants, E., & Das, R.
- Affiliations
- Eterna Massive Open Laboratory (US)
- Northwestern University (US)
- Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
- Stanford University (US)
- Corresponding author
- Das, Rhiju
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-09-14
- Volume
- 49
- Issue
- 18
- Pages
- 10604-10617
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC7457604
- OpenAlex
- W3200792349
- Cited by
- 197
- References
- 73
- Citations by year
- 2026: 35 · 2025: 51 · 2024: 35 · 2023: 31 · 2022: 27 · 2021: 16 · 2020: 2
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Stanford University Graduate Research Fellowship
- National Institutes of Health (R35 GM122579)
- FastGrants
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- mRNA stabilization, RNA hydrolysis, mRNA vaccines, mRNA therapeutics, SARS-CoV-2 spike protein, mRNA half-life
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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