The Messenger RNA (mRNA) Revolution: From Fundamental Biology to Therapeutic Applications and Future Horizons

Authors

  • Hussein Abouelhag Professor of Microbiology and Immunology at Department of Microbiology and Immunology, National Research Centre, Dokki, Giza, Egypt, 12622

DOI:

https://doi.org/10.33687/ricosbiol.04.01.106

Keywords:

mRNA, synthetic mRNA, mRNA therapeutics, lipid nanoparticles (LNPs), vaccinology, in vitro transcribed (IVT) mRNA, epitranscriptomics, RNA delivery, personalized medicine

Abstract

Messenger RNA (mRNA) has evolved from a fundamental biological intermediary to a versatile platform for therapeutic and prophylactic interventions. This review provides a comprehensive analysis of the mRNA field, beginning with the essential biology of natural mRNA processing and regulation. We detail the key engineering breakthroughs that transformed synthetic mRNA into a viable drug modality, including nucleoside modifications and sequence optimization to enhance stability and translational efficiency while modulating immunogenicity (Karikó, Buckstein, Ni, & Weissman, 2005; Pardi, Hogan, Porter, & Weissman, 2018). A critical discussion of delivery technologies, with a focus on lipid nanoparticles (LNPs), explains how these carriers enable in vivoapplication (Hou, Zaks, Langer, & Dong, 2021). The review then surveys the expansive therapeutic landscape, from the paradigm-shifting success of COVID-19 vaccines (Polack et al., 2020) to applications in protein replacement therapy, cancer immunotherapy, and gene editing. Finally, we examine persistent challenges—including delivery refinement, durability of response, and scaling manufacturing and envision future directions such as circular RNA, personalized neoantigen vaccines, and programmable protein therapeutics. The convergence of mRNA biology, chemistry, and delivery science heralds a new era in medicine with the potential to address a vast array of human diseases.

Downloads

Download data is not yet available.

Author Biography

  • Hussein Abouelhag, Professor of Microbiology and Immunology at Department of Microbiology and Immunology, National Research Centre, Dokki, Giza, Egypt, 12622
    Department of Microbiology and Immunology, National Research Centre, Dokki, Giza, Egypt, 12622

References

Abu Lila, A. S., Kiwada, H., & Ishida, T. (2013). The accelerated blood clearance (ABC) phenomenon: Clinical challenge and approaches to manage. Journal of Controlled Release, 172(1), 38–47. https://doi.org/10.1016/j.jconrel.2013.07.026

Akinc, A., Maier, M. A., Manoharan, M., Fitzgerald, K., Jayaraman, M., Barros, S., Ansell, S., Du, X., Hope, M. J., Madden, T. D., Mui, B. L., Semple, S. C., Tam, Y. K., Ciufolini, M., Witzigmann, D., Kulkarni, J. A., van der Meel, R., & Cullis, P. R. (2019). The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nature Nanotechnology, 14(12), 1084–1087. https://doi.org/10.1038/s41565-019-0591-y

Alexopoulou, L., Holt, A. C., Medzhitov, R., & Flavell, R. A. (2001). Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature, 413(6857), 732–738. https://doi.org/10.1038/35099560

Anderson, B. R., Muramatsu, H., Nallagatla, S. R., Bevilacqua, P. C., Sansing, L. H., Weissman, D., & Karikó, K. (2011). Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Research, 38(17), 5884–5892. https://doi.org/10.1093/nar/gkr347

Asrani, K. H., Farelli, J. D., Stahley, M. R., Miller, R. L., Cheng, C. J., Subramanian, R. R., & Brown, J. M. (2018). Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA. RNA Biology, 15(6), 756–762. https://doi.org/10.1080/15476286.2018.1450054

Baiersdörfer, M., Boros, G., Muramatsu, H., Mahiny, A., Vlatkovic, I., Sahin, U., & Karikó, K. (2019). A facile method for the removal of dsRNA contaminant from in vitro-transcribed mRNA. Molecular Therapy - Nucleic Acids, 15, 26–35. https://doi.org/10.1016/j.omtn.2019.02.018

Beckert, B., & Masquida, B. (2011). Synthesis of RNA by in vitro transcription. In RNA (pp. 29–41). Humana Press. https://doi.org/10.1007/978-1-59745-248-9_3

Belliveau, N. M., Huft, J., Lin, P. J., Chen, S., Leung, A. K., Leaver, T. J., Wild, A. W., Lee, J. B., Taylor, R. J., Tam, Y. K., Hansen, C. L., & Cullis, P. R. (2012). Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Molecular Therapy - Nucleic Acids, 1, e37. https://doi.org/10.1038/mtna.2012.28

Bloom, K., van den Berg, F., & Arbuthnot, P. (2021). Self-amplifying RNA vaccines for infectious diseases. Gene Therapy, 28(3–4), 117–129. https://doi.org/10.1038/s41434-020-00204-y

Brenner, S., Jacob, F., & Meselson, M. (1961). An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature, 190, 576–581. https://doi.org/10.1038/190576a0

Chen, R., & Wang, S. K. (2022). Circular RNAs in physiology and non-immunological diseases. Trends in Biochemical Sciences, 47(3), 250–264. https://doi.org/10.1016/j.tibs.2021.08.006

Cheng, Q., Wei, T., Jia, Y., Farbiak, L., Zhou, K., Zhang, S., Wei, Y., Zhu, H., & Siegwart, D. J. (2020). Dendrimer-based lipid nanoparticles deliver therapeutic FAH mRNA to normalize liver function and extend survival in a mouse model of hepatorenal tyrosinemia type I. Advanced Materials, 32(52), 2003537. https://doi.org/10.1002/adma.202003537

Corbett, K. S., Edwards, D. K., Leist, S. R., Abiona, O. M., Boyoglu-Barnum, S., Gillespie, R. A., Himansu, S., Schäfer, A., Ziwawo, C. T., DiPiazza, A. T., Dinnon, K. H., Elbashir, S. M., Shaw, C. A., Woods, A., Fritch, E. J., Martinez, D. R., Bock, K. W., Minai, M., Nagata, B. M., … Graham, B. S. (2020). SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature, 586(7830), 567–571. https://doi.org/10.1038/s41586-020-2622-0

Cullis, P. R., & Hope, M. J. (2017). Lipid nanoparticle systems for enabling gene therapies. Molecular Therapy, 25(7), 1467–1475. https://doi.org/10.1016/j.ymthe.2017.03.013

Dammes, N., & Peer, D. (2020). Paving the road for RNA therapeutics. Trends in Pharmacological Sciences, 41(10), 755–775. https://doi.org/10.1016/j.tips.2020.08.004

Dowdy, S. F. (2017). Overcoming cellular barriers for RNA therapeutics. Nature Biotechnology, 35(3), 222–229. https://doi.org/10.1038/nbt.3802

Eyler, D. E., Franco, M. K., Batool, Z., Wu, M. Z., Dubuke, M. L., Dobosz-Bartoszek, M., Jones, J. D., Polikanov, Y. S., Roy, B., & Koutmou, K. S. (2019). Pseudouridinylation of mRNA coding sequences alters translation. Proceedings of the National Academy of Sciences, 116(46), 23068–23074. https://doi.org/10.1073/pnas.1821754116

Finn, J. D., Smith, A. R., Patel, M. C., Shaw, L., Youniss, M. R., van Heteren, J., Dirstine, T., Ciullo, C., Lescarbeau, R., Seitzer, J., Shah, R. R., Shah, A., Ling, D., Growe, J., Pink, M., Rohde, E., Wood, K. M., Salomon, W. E., Harrington, W. F., … Morrissey, D. V. (2018). A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Reports, 22(9), 2227–2235. https://doi.org/10.1016/j.celrep.2018.02.014

Geall, A. J., Verma, A., Otten, G. R., Shaw, C. A., Hekele, A., Banerjee, K., Cu, Y., Beard, C. W., Brito, L. A., Krucker, T., O’Hagan, D. T., Singh, M., Mason, P. W., Valiante, N. M., Dormitzer, P. R., Barnett, S. W., Rappuoli, R., Ulmer, J. B., & Mandl, C. W. (2012). Nonviral delivery of self-amplifying RNA vaccines. Proceedings of the National Academy of Sciences, 109(36), 14604–14609. https://doi.org/10.1073/pnas.1209367109

Gustafsson, C., Govindarajan, S., & Minshull, J. (2004). Codon bias and heterologous protein expression. Trends in Biotechnology, 22(7), 346–353. https://doi.org/10.1016/j.tibtech.2004.04.006

Hassett, K. J., Benenato, K. E., Jacquinet, E., Lee, A., Woods, A., Yuzhakov, O., Himansu, S., Deterling, J., Geilich, B. M., Ketova, T., Mihai, C., Lynn, A., McFadyen, I., Moore, M. J., Senn, J. J., Stanton, M. G., Almarsson, Ö., Ciaramella, G., & Brito, L. A. (2021). Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Molecular Therapy - Nucleic Acids, 25, 1–11. https://doi.org/10.1016/j.omtn.2021.07.003

Henderson, J. M., Ujita, A., Hill, E., Yousif-Rosales, S., Smith, C., Ko, N., McReynolds, T., Cabral, C. R., Escamilla-Powers, J. R., & Houston, M. E. (2021). Cap 1 messenger RNA synthesis with co-transcriptional CleanCap® analog by in vitro transcription. Current Protocols, 1(2), e39. https://doi.org/10.1002/cpz1.39

Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K. K., Schlee, M., Endres, S., & Hartmann, G. (2006). 5'-Triphosphate RNA is the ligand for RIG-I. Science, 314(5801), 994–997. https://doi.org/10.1126/science.1132505

Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021). Lipid nanoparticles for mRNA delivery. Nature Reviews Materials, 6(12), 1078–1094. https://doi.org/10.1038/s41578-021-00358-0

Karikó, K., Buckstein, M., Ni, H., & Weissman, D. (2005). Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity, 23(2), 165–175. https://doi.org/10.1016/j.immuni.2005.06.008

Karikó, K., Muramatsu, H., Welsh, F. A., Ludwig, J., Kato, H., Akira, S., & Weissman, D. (2008). Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Molecular Therapy, 16(11), 1833–1840. https://doi.org/10.1038/mt.2008.200

Kis, Z., Shah, N., & Sato, Y. (2022). The future of vaccine manufacturing: Leveraging disruptive technologies to improve global health. Journal of Pharmaceutical Sciences, 111(5), 1241–1249. https://doi.org/10.1016/j.xphs.2021.12.013

Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019). Delivering the messenger: Advances in technologies for therapeutic mRNA delivery. Molecular Therapy, 27(4), 710–728. https://doi.org/10.1016/j.ymthe.2019.02.012

Laczko, D., Hogan, M. J., Toulmin, S. A., Hicks, P., Lederer, K., Gaudette, B. T., Castaño, D., Amanat, F., Muramatsu, H., Oguin, T. H., Ojha, A., Zhang, L., Mu, Z., Parks, R., Manzoni, T. B., Roper, B., Strohmeier, S., Tombácz, I., Arwood, L., … Weissman, D. (2020). A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in mice. Immunity, 53(4), 724-732.e7. https://doi.org/10.1016/j.immuni.2020.07.019

Leppek, K., Byeon, G. W., Kladwang, W., Wayment-Steele, H. K., Kerr, C. H., Xu, A. F., Kim, D. S., Topkar, V. V., Choe, C., Rothschild, D., Tiu, G. C., Wellington-Oguri, R., Fujii, K., Sharma, E., Watkins, A. M., Nicol, J. J., Romano, J., Tunguz, B., Diaz, F., … Das, R. (2022). Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics. Nature Communications, 13(1), 1536. https://doi.org/10.1038/s41467-022-28776-w

Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018). mRNA vaccines — a new era in vaccinology. Nature Reviews Drug Discovery, 17(4), 261–279. https://doi.org/10.1038/nrd.2017.243

Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., Zerbini, C., Bailey, R., Swanson, K. A., Roychoudhury, S., Koury, K., Li, P., Kalina, W. V., Cooper, D., Frenck, R. W., Hammitt, L. L., … Gruber, W. C. (2020). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 383(27), 2603–2615. https://doi.org/10.1056/NEJMoa2034577

Rohner, E., Yang, R., Foo, K. S., Goedel, A., & Chien, K. R. (2022). Unlocking the promise of mRNA therapeutics. Nature Biotechnology, 40(11), 1586–1600. https://doi.org/10.1038/s41587-022-01491-z

Sahin, U., Oehm, P., Derhovanessian, E., Jabulowsky, R. A., Vormehr, M., Gold, M., Maurus, D., Schwarck-Kokarakis, D., Kuhn, A. N., Omokoko, T., Kranz, L. M., Diken, M., Kreiter, S., Haas, H., Attig, S., Rae, R., Cuk, K., Kemmer-Brück, A., Breitkreuz, A., … Türeci, Ö. (2020). An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature, 585(7823), 107–112. https://doi.org/10.1038/s41586-020-2537-8

Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W., Stebbing, D., Crosley, E. J., Yaworski, E., Hafez, I. M., Dorkin, J. R., Qin, J., Lam, K., Rajeev, K. G., Wong, K. F., Jeffs, L. B., Nechev, L., Eisenhardt, M. L., … Hope, M. J. (2010). Rational design of cationic lipids for siRNA delivery. Nature Biotechnology, 28(2), 172–176. https://doi.org/10.1038/nbt.1602

Springer, A. D., & Dowdy, S. F. (2018). GalNAc-siRNA conjugates: Leading the way for delivery of RNAi therapeutics. Nucleic Acid Therapeutics, 28(3), 109–118. https://doi.org/10.1089/nat.2018.0736

Stepinski, J., Waddell, C., Stolarski, R., Darzynkiewicz, E., & Rhoads, R. E. (2001). Synthesis and properties of mRNAs containing the novel "anti-reverse" cap analogs 7-methyl(3'-O-methyl)GpppG and 7-methyl (3'-deoxy)GpppG. RNA, 7(10), 1486–1495. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1370193/

Udhayakumar, V. K., De Beuckelaer, A., McCaffrey, J., McCrudden, C. M., Kirschman, J. L., Vanover, D., Van Hoecke, L., Roose, K., Deswarte, K., De Geest, B. G., Lienenklaus, S., & De Koker, S. (2021). Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide. Advanced Healthcare Materials, 10(7), 2001652. https://doi.org/10.1002/adhm.202001652

Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., Daley, G. Q., Brack, A. S., Collins, J. J., Cowan, C., Schlaeger, T. M., & Rossi, D. J. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7(5), 618–630. https://doi.org/10.1016/j.stem.2010.08.012

Weissman, D., Pardi, N., Muramatsu, H., & Karikó, K. (2013). HPLC purification of in vitro transcribed long RNA. Methods in Molecular Biology, 969, 43–54. https://doi.org/10.1007/978-1-62703-260-5_3

Wesselhoeft, R. A., Kowalski, P. S., Parker-Hale, F. C., Huang, Y., Biswas, S., & Anderson, D. G. (2019). RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Molecular Cell, 74(3), 508-520.e4. https://doi.org/10.1016/j.molcel.2019.02.015

Wolff, J. A., Malone, R. W., Williams, P., Chong, W., Acsadi, G., Jani, A., & Felgner, P. L. (1990). Direct gene transfer into mouse muscle in vivo. Science, 247(4949 Pt 1), 1465–1468. https://doi.org/10.1126/science.1690918

Zangi, L., Lui, K. O., von Gise, A., Ma, Q., Ebina, W., Ptaszek, L. M., Später, D., Xu, H., Tabebordbar, M., Gorbatov, R., Sena, B., Nahrendorf, M., Briscoe, D. M., Li, R. A., Wagers, A. J., Rossi, D. J., Pu, W. T., & Chien, K. R. (2013). Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nature Biotechnology, 31(10), 898–907. https://doi.org/10.1038/nbt.2682

Downloads

Published

31-01-2026

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study. All material reviewed is based on existing published literature referenced accordingly.

How to Cite

The Messenger RNA (mRNA) Revolution: From Fundamental Biology to Therapeutic Applications and Future Horizons. (2026). Ricos Biology, 4(1), 1-11. https://doi.org/10.33687/ricosbiol.04.01.106

Similar Articles

31-40 of 55

You may also start an advanced similarity search for this article.

Most read articles by the same author(s)

1 2 3 > >>