Tailor made: the art of therapeutic mRNA design


  • Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R. & Anderson, D. G. The clinical progress of mRNA vaccines and immunotherapies. Nat. Biotechnol. 40, 840–854 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lindsay, K. E. et al. Visualization of early events in mRNA vaccine delivery in non-human primates via PET–CT and near-infrared imaging. Nat. Biomed. Eng. 3, 371–380 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Vavilis, T. et al. mRNA in the context of protein replacement therapy. Pharmaceutics 15, 166 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Meyer, R. A., Neshat, S. Y., Green, J. J., Santos, J. L. & Tuesca, A. D. Targeting strategies for mRNA delivery. Mater. Today Adv. 14, 100240 (2022).

    Article 
    CAS 

    Google Scholar 

  • Paunovska, K., Loughrey, D. & Dahlman, J. E. Drug delivery systems for RNA therapeutics. Nat. Rev. Genet. 23, 265–280 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Morris, C., Cluet, D. & Ricci, E. P. Ribosome dynamics and mRNA turnover, a complex relationship under constant cellular scrutiny. Wiley Iinterdiscip. Rev. RNA 12, e1658 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mercier, B. C. et al. Translation-dependent and independent mRNA decay occur through mutually exclusive pathways that are defined by ribosome density during T cell activation. Preprint at bioRxiv https://doi.org/10.1101/2020.10.16.341222 (2020).

  • Villanueva, J. C. How Many Atoms Are There in the Universe? Universe Today https://www.universetoday.com/36302/atoms-in-the-universe/ (2009).

  • Hanson, G. & Coller, J. Codon optimality, bias and usage in translation and mRNA decay. Nat. Rev. Mol. Cell Biol. 19, 20–30 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hanson, G., Alhusaini, N., Morris, N., Sweet, T. & Coller, J. Translation elongation and mRNA stability are coupled through the ribosomal A-site. RNA 24, 1377–1389 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bae, H. & Coller, J. Codon optimality-mediated mRNA degradation: linking translational elongation to mRNA stability. Mol. Cell 82, 1467–1476 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zolotukhin, S., Potter, M., Hauswirth, W. W., Guy, J. & Muzyczka, N. A ‘humanized’ green fluorescent protein cDNA adapted for high-level expression in mammalian cells. J. Virol. 70, 4646–4654 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kudla, G., Lipinski, L., Caffin, F., Helwak, A. & Zylicz, M. High guanine and cytosine content increases mRNA levels in mammalian cells. PLoS Biol. 4, e180 (2006).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mordstein, C. et al. Codon usage and splicing jointly influence mRNA localization. Cell Syst. 10, 351–362.e8 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Thess, A. et al. Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol. Ther. 23, 1456–1464 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Parvathy, S. T., Udayasuriyan, V. & Bhadana, V. Codon usage bias. Mol. Biol. Rep. 49, 539–565 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sharp, P. M. & Li, W. H. The codon adaptation index—a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res. 15, 1281–1295 (1987).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Reis, M., dos, Savva, R. & Wernisch, L. Solving the riddle of codon usage preferences: a test for translational selection. Nucleic Acids Res. 32, 5036–5044 (2004).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Forrest, M. E. et al. Codon and amino acid content are associated with mRNA stability in mammalian cells. PLoS ONE 15, e0228730 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dittmar, K. A., Goodenbour, J. M. & Pan, T. Tissue-specific differences in human transfer RNA expression. PLoS Genet. 2, e221 (2006).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pinkard, O., McFarland, S., Sweet, T. & Coller, J. Quantitative tRNA-sequencing uncovers metazoan tissue-specific tRNA regulation. Nat. Commun. 11, 4104 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tuller, T. et al. An evolutionarily conserved mechanism for controlling the efficiency of protein translation. Cell 141, 344–354 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sejour, R., Leatherwood, J., Yurovsky, A. & Futcher, B. No ramp needed: spandrels, statistics, and a slippery slope. eLife 12, RP89656 (2023).

    Google Scholar 

  • Mortimer, S. A., Kidwell, M. A. & Doudna, J. A. Insights into RNA structure and function from genome-wide studies. Nat. Rev. Genet. 15, 469–479 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Leppek, K. et al. Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics. Nat. Commun. 13, 1536 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, H. et al. Algorithm for optimized mRNA design improves stability and immunogenicity. Nature 621, 396–403 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tanzer, A., Hofacker, I. L. & Lorenz, R. RNA modifications in structure prediction – status quo and future challenges. Methods 156, 32–39 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mauger, D. M. et al. mRNA structure regulates protein expression through changes in functional half-life. Proc. Natl Acad. Sci. USA 116, 24075–24083 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kierzek, E. et al. Secondary structure prediction for RNA sequences including N6-methyladenosine. Nat. Commun. 13, 1271 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Turner, D. H., Sugimoto, N. & Freier, S. M. RNA structure prediction. Annu. Rev. Biophys. Biophys. Chem. 17, 167–192 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Turner, D. H. Thermodynamics of base pairing. Curr. Opin. Struct. Biol. 6, 299–304 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pleij, C. W., Rietveld, K. & Bosch, L. A new principle of RNA folding based on pseudoknotting. Nucleic Acids Res. 13, 1717–1731 (1985).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zuber, J., Schroeder, S. J., Sun, H., Turner, D. H. & Mathews, D. H. Nearest neighbor rules for RNA helix folding thermodynamics: improved end effects. Nucleic Acids Res. 50, 5251–5262 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xia, T. et al. Thermodynamic parameters for an expanded nearest-neighbor model for formation of RNA duplexes with Watson−Crick base pairs. Biochemistry 37, 14719–14735 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Andronescu, M., Condon, A., Turner, D. H. & Mathews, D. H. The determination of RNA folding nearest neighbor parameters. Methods Mol. Biol. 1097, 45–70 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Raden, M., Mohamed, M. M., Ali, S. M. & Backofen, R. Interactive implementations of thermodynamics-based RNA structure and RNA–RNA interaction prediction approaches for example-driven teaching. PLOS Comput. Biol. 14, e1006341 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hofacker, I. L., Schuster, P. & Stadler, P. F. Combinatorics of RNA secondary structures. Discret. Appl. Math. 88, 207–237 (1998).

    Article 

    Google Scholar 

  • Mathews, D. H. Using an RNA secondary structure partition function to determine confidence in base pairs predicted by free energy minimization. RNA 10, 1178–1190 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yu, H., Qi, Y. & Ding, Y. Deep learning in RNA structure studies. Front. Mol. Biosci. 9, 869601 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lu, Z. J., Gloor, J. W. & Mathews, D. H. Improved RNA secondary structure prediction by maximizing expected pair accuracy. RNA 15, 1805–1813 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Szikszai, M., Wise, M., Datta, A., Ward, M. & Mathews, D. H. Deep learning models for RNA secondary structure prediction (probably) do not generalise across families. Bioinformatics 38, 3892–3899 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Flamm, C. et al. Caveats to deep learning approaches to RNA secondary structure prediction. Front. Bioinform. 2, 835422 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Trotta, E. On the normalization of the minimum free energy of RNAs by sequence length. PLoS ONE 9, e113380 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huynen, M., Gutell, R. & Konings, D. Assessing the reliability of RNA folding using statistical mechanics. J. Mol. Biol. 267, 1104–1112 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yu, A. M. et al. Computationally reconstructing cotranscriptional RNA folding from experimental data reveals rearrangement of non-native folding intermediates. Mol. Cell 81, 870–883.e10 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huang, X. et al. The landscape of mRNA nanomedicine. Nat. Med. 28, 2273–2287 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).

    Article 
    PubMed 

    Google Scholar 

  • Andries, O. et al. N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J. Control. Release 217, 337–344 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Nelson, J. et al. Impact of mRNA chemistry and manufacturing process on innate immune activation. Sci. Adv. 6, eaaz6893 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Morais, P., Adachi, H. & Yu, Y.-T. The critical contribution of pseudouridine to mRNA COVID-19 vaccines. Front. Cell Dev. Biol. 9, 789427 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Alameh, M.-G. & Weissman, D. Chapter 7 – Nucleoside modifications of in vitro transcribed mRNA to reduce immunogenicity and improve translation of prophylactic and therapeutic antigens. in RNA Therapeutics (eds. Giangrande, P. H., de Franciscis, V. & Rossi, J. J.) 141–169 (Academic Press, 2022).

  • Liu, A. & Wang, X. The pivotal role of chemical modifications in mRNA therapeutics. Front. Cell Dev. Biol. 10, 901510 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brand, R. C., Klootwijk, J., Planta, R. J. & Maden, B. E. H. Biosynthesis of a hypermodified nucleotide in Saccharomyces carlsbergensis 17S and HeLa-cell 18S ribosomal ribonucleic acid. Biochem. J. 169, 71–77 (1978).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wurm, J. P. et al. The ribosome assembly factor Nep1 responsible for Bowen–Conradi syndrome is a pseudouridine-N1-specific methyltransferase. Nucleic Acids Res. 38, 2387–2398 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gilbert, W. V. & Nachtergaele, S. mRNA regulation by RNA modifications. Annu. Rev. Biochem. 92, 175–198 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Huang, S. et al. Interferon inducible pseudouridine modification in human mRNA by quantitative nanopore profiling. Genome Biol. 22, 330 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, T., Potapov, V., Dai, N., Ong, J. L. & Roy, B. N1-methyl-pseudouridine is incorporated with higher fidelity than pseudouridine in synthetic RNAs. Sci. Rep. 12, 13017 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eyler, D. E. et al. Pseudouridinylation of mRNA coding sequences alters translation. Proc. Natl Acad. Sci. USA 116, 23068–23074 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, K. Q. et al. N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products. Cell Rep. 40, 111300 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Szabat, M., Prochota, M., Kierzek, R., Kierzek, E. & Mathews, D. H. A test and refinement of folding free energy nearest neighbor parameters for RNA including N6-methyladenosine. J. Mol. Biol. 434, 167632 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Liu, J. & Cao, X. RBP–RNA interactions in the control of autoimmunity and autoinflammation. Cell Res. 33, 97–115 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Boo, S. H. & Kim, Y. K. The emerging role of RNA modifications in the regulation of mRNA stability. Exp. Mol. Med. 52, 400–408 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • D’Esposito, R. J., Myers, C. A., Chen, A. A. & Vangaveti, S. Challenges with simulating modified RNA: insights into role and reciprocity of experimental and computational approaches. Genes 13, 540 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hopfinger, M. C., Kirkpatrick, C. C. & Znosko, B. M. Predictions and analyses of RNA nearest neighbor parameters for modified nucleotides. Nucleic Acids Res. 48, 8901–8913 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pelletier, J. & Sonenberg, N. The organizing principles of eukaryotic ribosome recruitment. Annu. Rev. Biochem. 88, 307–335 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Shirokikh, N. E. & Preiss, T. Translation initiation by cap-dependent ribosome recruitment: recent insights and open questions. Wiley Interdiscip. Rev. RNA 9, e1473 (2018).

    Article 
    PubMed 

    Google Scholar 

  • Ringnér, M. & Krogh, M. Folding free energies of 5′-UTRs impact post-transcriptional regulation on a genomic scale in yeast. PLoS Comput. Biol. 1, e72 (2005).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Babendure, J. R. Control of mammalian translation by mRNA structure near caps. RNA 12, 851–861 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kozak, M. Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Mol. Cell. Biol. 9, 5134–5142 (1989).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kumari, S., Bugaut, A. & Balasubramanian, S. Position and stability are determining factors for translation repression by an RNA G-quadruplex-forming sequence within the 5′ UTR of the NRAS proto-oncogene. Biochemistry 47, 12664–12669 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sample, P. J. et al. Human 5′ UTR design and variant effect prediction from a massively parallel translation assay. Nat. Biotechnol. 37, 803 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Leppek, K., Das, R. & Barna, M. Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat. Rev. Mol. Cell Biol. 19, 158–174 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, J. et al. Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation. Cell 185, 4474–4487.e17 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dave, P. et al. Single-molecule imaging reveals translation-dependent destabilization of mRNAs. Mol. Cell 83, 589–606.e6 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Piccinelli, P. & Samuelsson, T. Evolution of the iron-responsive element. RNA 13, 952–966 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gray, N. K. & Hentze, M. W. Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs. EMBO J. 13, 3882–3891 (1994).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hentze, M. et al. Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science 238, 1570–1573 (1987).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Muckenthaler, M. U., Rivella, S., Hentze, M. W. & Galy, B. A red carpet for iron metabolism. Cell 168, 344–361 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kavita, K. & Breaker, R. R. Discovering riboswitches: the past and the future. Trends Biochem, Sci. 48, 119–141 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mustafina, K., Fukunaga, K. & Yokobayashi, Y. Design of mammalian ON-riboswitches based on tandemly fused aptamer and ribozyme. ACS Synth. Biol. 9, 19–25 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pelletier, J., Graff, J., Ruggero, D. & Sonenberg, N. Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res. 75, 250–263 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vaklavas, C., Blume, S. W. & Grizzle, W. E. Translational dysregulation in cancer: molecular insights and potential clinical applications in biomarker development. Front. Oncol. 7, 158 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Raza, F., Waldron, J. A. & Quesne, J. L. Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence. Biochem. Soc. Trans. 43, 1227–1233 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Schmidt, T. et al. eIF4A1-dependent mRNAs employ purine-rich 5′UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation. Nucleic Acids Res. 51, 1859–1879 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fath, S. et al. Multiparameter RNA and codon optimization: a standardized tool to assess and enhance autologous mammalian gene expression. PLoS ONE 6, e17596 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, S. et al. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. Proc. Natl Acad. Sci. USA 109, E2424–E2432 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kozak, M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 15, 8125–8148 (1987).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Simonetti, A., Guca, E., Bochler, A., Kuhn, L. & Hashem, Y. Structural insights into the mammalian late-stage initiation complexes. Cell Rep. 31, 107497 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kozak, M. Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. Proc. Natl Acad. Sci. USA 87, 8301–8305 (1990).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kochetov, A. V. et al. AUG_hairpin: prediction of a downstream secondary structure influencing the recognition of a translation start site. BMC Bioinformatics 8, 318 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liang, H. et al. PTENβ is an alternatively translated isoform of PTEN that regulates rDNA transcription. Nat. Commun. 8, 14771 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gu, W., Zhou, T. & Wilke, C. O. A universal trend of reduced mRNA stability near the translation-initiation site in prokaryotes and eukaryotes. PLoS Comput. Biol. 6, e1000664 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, F. et al. Global analysis of RNA secondary structure in two metazoans. Cell Rep. 1, 69–82 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wan, Y. et al. Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505, 706–709 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shabalina, S. A., Ogurtsov, A. Y. & Spiridonov, N. A. A periodic pattern of mRNA secondary structure created by the genetic code. Nucleic Acids Res. 34, 2428–2437 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Toribio, R., Díaz-López, I., Boskovic, J. & Ventoso, I. An RNA trapping mechanism in Alphavirus mRNA promotes ribosome stalling and translation initiation. Nucleic Acids Res. 44, 4368–4380 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Clote, P., Ponty, Y. & Steyaert, J.-M. Expected distance between terminal nucleotides of RNA secondary structures. J. Math. Biol. 65, 581–599 (2012).

    Article 
    PubMed 

    Google Scholar 

  • Yoffe, A. M., Prinsen, P., Gelbart, W. M. & Ben-Shaul, A. The ends of a large RNA molecule are necessarily close. Nucleic Acids Res. 39, 292–299 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Simms, C. L., Yan, L. L. & Zaher, H. S. Ribosome collision is critical for quality control during no-go decay. Mol. Cell 68, 361–373.e5 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Saito, K. et al. Ribosome collisions induce mRNA cleavage and ribosome rescue in bacteria. Nature 603, 503–508 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wu, C. C.-C., Peterson, A., Zinshteyn, B., Regot, S. & Green, R. Ribosome collisions trigger general stress responses to regulate cell fate. Cell 182, 404–416.e14 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gorochowski, T. E., Ignatova, Z., Bovenberg, R. A. L. & Roubos, J. A. Trade-offs between tRNA abundance and mRNA secondary structure support smoothing of translation elongation rate. Nucleic Acids Res. 43, 3022–3032 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chaney, J. L. & Clark, P. L. Roles for synonymous codon usage in protein biogenesis. Annu. Rev. Biophys. 44, 143–166 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Collart, M. A. & Weiss, B. Ribosome pausing, a dangerous necessity for co-translational events. Nucleic Acids Res. 48, 1043–1055 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • D’Orazio, K. N. & Green, R. Ribosome states signal RNA quality control. Mol. Cell 81, 1372–1383 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Arpat, A. B. et al. Transcriptome-wide sites of collided ribosomes reveal principles of translational pausing. Genome Res. 30, 985–999 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhao, T. et al. Disome-seq reveals widespread ribosome collisions that promote cotranslational protein folding. Genome Biol. 22, 16 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, Y. & Bebok, Z. An examination of mechanisms by which synonymous mutations may alter protein levels, structure and functions. in Single Nucleotide Polymorphisms: Human Variation and a Coming Revolution in Biology and Medicine (eds. Sauna, Z. E. & Kimchi-Sarfaty, C.) 99–132 (Springer International Publishing, 2022).

  • Lin, B. C., Kaissarian, N. M. & Kimchi-Sarfaty, C. Implementing computational methods in tandem with synonymous gene recoding for therapeutic development. Trends Pharmacol. Sci. 44, 73–84 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Chen, Y. G. & Hur, S. Cellular origins of dsRNA, their recognition and consequences. Nat. Rev. Mol. Cell Biol. 23, 286–301 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wuebben, C., Bartok, E. & Hartmann, G. Innate sensing of mRNA vaccines. Curr. Opin. Immunol. 79, 102249 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mu, X. & Hur, S. Immunogenicity of in vitro-transcribed RNA. Acc. Chem. Res. 54, 4012–4023 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dousis, A., Ravichandran, K., Hobert, E. M., Moore, M. J. & Rabideau, A. E. An engineered T7 RNA polymerase that produces mRNA free of immunostimulatory byproducts. Nat. Biotechnol. 41, 560–568 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Weissman, D., Pardi, N., Muramatsu, H. & Karikó, K. HPLC purification of in vitro transcribed long RNA. Methods Mol. Biol. 969, 43–54 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Das, S., Vera, M., Gandin, V., Singer, R. H. & Tutucci, E. Intracellular mRNA transport and localized translation. Nat. Rev. Mol. Cell Biol. 22, 483–504 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ermolenko, D. N. & Mathews, D. H. Making ends meet: new functions of mRNA secondary structure. Wiley Interdiscip. Rev. RNA 12, e1611 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tan, D., Marzluff, W. F., Dominski, Z. & Tong, L. Structure of histone mRNA stem-loop, human stem-loop binding protein and 3′hExo ternary complex. Science 339, 318–321 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Marzluff, W. F. & Koreski, K. P. Birth and death of histone mRNAs. Trends Genet. 33, 745–759 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gorgoni, B. et al. The stem–loop binding protein stimulates histone translation at an early step in the initiation pathway. RNA 11, 1030–1042 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Choe, J., Ahn, S. H. & Kim, Y. K. The mRNP remodeling mediated by UPF1 promotes rapid degradation of replication-dependent histone mRNA. Nucleic Acids Res. 42, 9334–9349 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Thess, A., Schlake, T. & Probst, J. US patent US20200345831A1 (2020).

  • Gebre, M. S. et al. Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine. Nature 601, 410–414 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Miras, M., Miller, W. A., Truniger, V. & Aranda, M. A. Non-canonical translation in plant RNA viruses. Front. Plant Sci. 8, 494 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, D. et al. Viral hijacking of the TENT4–ZCCHC14 complex protects viral RNAs via mixed tailing. Nat. Struct. Mol. Biol. 27, 581–588 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Krawczyk, P. S. et al. SARS-CoV-2 mRNA vaccine is re-adenylated in vivo, enhancing antigen production and immune response. Preprint at bioRxiv https://doi.org/10.1101/2022.12.01.518149 (2022).

  • Miyazawa, M., Bogdan, A. R., Hashimoto, K. & Tsuji, Y. Regulation of transferrin receptor-1 mRNA by the interplay between IRE-binding proteins and miR-7/miR-141 in the 3′-IRE stem–loops. RNA 24, 468–479 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jain, R. et al. MicroRNAs enable mRNA therapeutics to selectively program cancer cells to self-destruct. Nucleic Acid. Ther. 28, 285–296 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hagedorn, P. H., Hansen, B. R., Koch, T. & Lindow, M. Managing the sequence-specificity of antisense oligonucleotides in drug discovery. Nucleic Acids Res. 45, 2262–2282 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Orlandini von Niessen, A. G. et al. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening. Mol. Ther. 27, 824–836 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Solodushko, V. & Fouty, B. Terminal hairpins improve protein expression in IRES-initiated mRNA in the absence of a cap and polyadenylated tail. Gene Ther. 30, 620–627 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shanmugasundaram, M., Senthilvelan, A. & Kore, A. R. Recent advances in modified cap analogs: synthesis, biochemical properties, and mRNA based vaccines. Chem. Rec. 22, e202200005 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Deal, C. E. et al. mRNA delivery of dimeric human IgA protects mucosal tissues from bacterial infection. Preprint at bioRxiv https://doi.org/10.1101/2023.01.03.521487 (2023).

  • Liu, C.-X. & Chen, L.-L. Circular RNAs: characterization, cellular roles, and applications. Cell 185, 2016–2034 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ren, L. et al. Mechanisms of circular RNA degradation. Commun. Biol. 5, 1355 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Enuka, Y. et al. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 44, 1370–1383 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mailliot, J. & Martin, F. Viral internal ribosomal entry sites: four classes for one goal. Wiley Interdiscip. Rev. RNA 9, e1458 (2018).

    Article 

    Google Scholar 

  • Jaafar, Z. A. & Kieft, J. S. Viral RNA structure-based strategies to manipulate translation. Nat. Rev. Microbiol. 17, 110–123 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Qu, L. et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell 185, 1728–1744.e16 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wellensiek, B. P. et al. Genome-wide profiling of human cap-independent translation-enhancing elements. Nat. Methods 10, 747–750 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Weingarten-Gabbay, S. et al. Systematic discovery of cap-independent translation sequences in human and viral genomes. Science 351, aad4939 (2016).

    Article 
    PubMed 

    Google Scholar 

  • Chen, C.-K. et al. Structured elements drive extensive circular RNA translation. Mol. Cell 81, 4300–4318.e13 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Akirtava, C. & McManus, C. J. Control of translation by eukaryotic mRNA transcript leaders-Insights from high-throughput assays and computational modeling. Wiley Interdiscip. Rev. RNA 12, e1623 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Jackson, R. J. The current status of vertebrate cellular mRNA IRESs. Cold Spring Harb. Perspect. Biol. 5, a011569 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Busa, V. F. & Leung, A. K. L. Thrown for a (stem) loop: how RNA structure impacts circular RNA regulation and function. Methods 196, 56–67 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Liu, C. et al. Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell 177, 865–880.e21 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Comes, J. D. G., Pijlman, G. P. & Hick, T. A. H. Rise of the RNA machines – self-amplification in mRNA vaccine design. Trends Biotechnol. 41, 1417–1421 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Li, Y. & Breaker, R. R. Kinetics of RNA degradation by specific base catalysis of transesterification involving the 2′-hydroxyl group. J. Am. Chem. Soc. 121, 5364–5372 (1999).

    Article 
    CAS 

    Google Scholar 

  • Packer, M., Gyawali, D., Yerabolu, R., Schariter, J. & White, P. A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems. Nat. Commun. 12, 6777 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Oude Blenke, E. et al. The storage and in-use stability of mRNA vaccines and therapeutics: not a cold case. J. Pharm. Sci. 112, 386–403 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cheng, F. et al. Research advances on the stability of mRNA vaccines. Viruses 15, 668 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guo, F. et al. Effect of ribose conformation on RNA cleavage via internal transesterification. J. Am. Chem. Soc. 140, 11893–11897 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hernandez-Alias, X., Benisty, H., Radusky, L. G., Serrano, L. & Schaefer, M. H. Using protein-per-mRNA differences among human tissues in codon optimization. Genome Biol. 24, 34 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Behrens, A., Rodschinka, G. & Nedialkova, D. D. High-resolution quantitative profiling of tRNA abundance and modification status in eukaryotes by mim-tRNAseq. Mol. Cell 81, 1802–1815.e7 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brader, M. L. et al. Encapsulation state of messenger RNA inside lipid nanoparticles. Biophys. J. 120, 2766–2770 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Castillo-Hair, S. M. & Seelig, G. Machine learning for designing next-generation mRNA therapeutics. Acc. Chem. Res. 55, 24–34 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug. Discov. 17, 261–279 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • New England Biolabs. mRNA capping. NEB, https://www.neb.com/products/rna-reagents/rna-synthesis/rna-synthesis/rna-capping (2023).

  • Chan, S.-H. & Roy, B. Preparation of synthetic mRNAs—overview and considerations. In Messenger RNA Therapeutics (eds. Jurga, S. & Barciszewski, J.) 181–207 (Springer International Publishing, 2022).

  • Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug. Discov. 13, 759–780 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Trepotec, Z., Geiger, J., Plank, C., Aneja, M. K. & Rudolph, C. Segmented poly(A) tails significantly reduce recombination of plasmid DNA without affecting mRNA translation efficiency or half-life. RNA 25, 507–518 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bundschuh, R. & Gerland, U. Dynamics of intramolecular recognition: base-pairing in DNA/RNA near and far from equilibrium. Eur. Phys. J. E 19, 319–329 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kim, G.-W. & Siddiqui, A. N6-methyladenosine modification of HCV RNA genome regulates cap-independent IRES-mediated translation via YTHDC2 recognition. Proc. Natl Acad. Sci. USA 118, e2022024118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Quade, N., Boehringer, D., Leibundgut, M., van den Heuvel, J. & Ban, N. Cryo-EM structure of hepatitis C virus IRES bound to the human ribosome at 3.9-Å resolution. Nat. Commun. 6, 7646 (2015).

    Article 
    PubMed 

    Google Scholar 

  • He, M. et al. Bio-orthogonal chemistry enables solid phase synthesis and HPLC and gel-free purification of long RNA oligonucleotides. Chem. Commun. 57, 4263–4266 (2021).

    Article 
    CAS 

    Google Scholar 

  • Ganser, L. R., Kelly, M. L., Herschlag, D. & Al-Hashimi, H. M. The roles of structural dynamics in the cellular functions of RNAs. Nat. Rev. Mol. Cell Biol. 20, 474–489 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, Q., Fairman, M. E. & Jankowsky, E. DEAD-box-protein-assisted RNA structure conversion towards and against thermodynamic equilibrium values. J. Mol. Biol. 368, 1087–1100 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Singh, G., Pratt, G., Yeo, G. W. & Moore, M. J. The clothes make the mRNA: past and present trends in mRNP fashion. Annu. Rev. Biochem. 84, 325–354 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Metkar, M. et al. Higher-order organization principles of pre-translational mRNPs. Mol. Cell 72, 715–726.e3 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sun, L. et al. RNA structure maps across mammalian cellular compartments. Nat. Struct. Mol. Biol. 26, 322–330 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, S. et al. The regulatory impact of RNA-binding proteins on microRNA targeting. Nat. Commun. 12, 5057 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 



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