Designing mRNA For The Next Generation Of Therapeutics

By Carol Tan-Fujita, Ph.D., and Archa Fox, Ph.D., Australian Centre for RNA Therapeutics in Cancer (ACRTC) and the RNA Innovation Foundry (RIF), The University of Western Australia

Most scientists would agree that messenger RNA (mRNA) has transformed how the world thinks about vaccines. But its real disruptive potential may lie in a quieter revolution now gaining momentum: the use of mRNAs as programmable therapeutics capable of expressing proteins in vivo with finely tuned longevity, intensity, and tissue specificity. Compared with the fast, transient spike expression in prophylactic vaccines, durable and controlled expression for chronic or regenerative indications requires a fundamental rethink of how mRNAs are engineered and optimized.

From Emergency Vaccines To Enduring Medicines

The COVID-19 era established mRNA as a clinically and commercially viable modality, but those first-generation vaccines were intentionally short-lived and immunostimulatory, reflecting both their prophylactic purpose and accelerated development timelines. For vaccines, brief antigen expression is sufficient — and often desirable — to prime adaptive immunity while limiting exposure.

Therapeutic mRNAs, by contrast, are being developed for a myriad of indications. In many of these settings, clinical benefit depends on sustaining expression and protein production or matching expression kinetics to a defined therapeutic window. The design goal shifts from maximizing peak expression to shaping expression profiles over time.

The therapeutic promise of mRNA rests on achieving the right balance between expression and degradation. Too short a half-life necessitates frequent or high-dose administration, while overly persistent expression can drive immunogenicity or tolerability concerns. Excessive or prolonged protein production may stress cells, saturate downstream pathways, or overstimulate immune responses — challenges that become especially pronounced in chronic dosing regimens.​

This balance is further complicated by the innate immune system. Exogenous mRNA can trigger pattern recognition receptors (PRRs), including toll-like receptors (TLRs), leading to inflammation and accelerated degradation. While nucleoside modifications such as pseudouridine — recognized by the 2023 Nobel Prize in Medicine awarded to Katalin Kariko and Drew Weissman — substantially dampen innate immune recognition, they do not eliminate detection entirely.

It’s More Than Just Delivery

Formulation and delivery systems have rightly commanded much of the spotlight in the mRNA era. They determine biodiversification, endosomal escape efficiency, and interactions with innate sensors, all of which undeniably shape therapeutic outcomes. Yet, focusing exclusively on delivery risks sidelining an equally critical dimension: the intrinsic design/properties of the mRNA payload itself.

Traditional sequence-optimization strategies are widely adopted and well understood. However, these approaches often fall short for applications requiring sustained expression or precise control over translation kinetics. The prevailing “plug-and-play” mindset underappreciates how the full-length mRNA sequences fold into complex secondary and tertiary structures that dictate stability, translational kinetics, and eventual decay.

Tuning The mRNA

mRNA design extends far beyond the open reading frame and base chemistry. The 5’ and 3’ untranslated regions (UTRs), cap structure, and poly(A) tail are all known to affect how long an mRNA survives and how efficiently it translates — though no single configuration performs optimally across all cell types or disease contexts. UTRs derived from naturally long-lived transcripts, such as α-globin, are routinely used to enhance stability and protein output. Advanced cap structures, such as Cap1 chemistry and optimized poly(A) tails, further support efficient initiation, ribosome recycling, and protection from machine decay.

Sequence composition also affects manufacturability. High GC content, repetitive motifs, or secondary structures can impact in vitro transcription and purification.

Like proteins folding into precise 3D shapes dictating function, mRNAs adopt intricate structures — stem-loops, pseudoknots, and long-range interactions — that influence both longevity and output. A compact fold may prolong half-life by resisting degradation yet inhibit translation by occluding the Kozak sequence. Conversely, unfolded stretches may boost initial output but accelerate clearance. Unlike proteins, whose 3D structures are relatively stable, mRNA structures are dynamic and environment-sensitive. As a result, rational mRNA design must account for cellular context, intended protein function, and both global and local RNA architecture to proactively and appropriately tune performance.

Emerging strategies go beyond optimizing individual components, introducing entirely new RNA formats. Self-amplifying mRNAs (saRNAs) encode viral replicase machinery that allows saRNA to be copied within the host cell. Circular RNAs (cRNAs), formed by covalently linking the 3’ and 5’ ends, resist exonuclease-mediated degradation and can sustain protein production from lower input doses.

Synthetic biology is further expanding the design space by “programming” mRNA behavior. Strand Therapeutics, for example, has developed genetic logic circuits that activate translation only in defined cellular environments. Radar Therapeutics has introduced regulatory switches within mRNA designs that harness a cell’s own RNA-editing enzymes to drive cell-type specific translation of the mRNA. In these systems, the mRNAs are engineered to “sense” their own output or the cellular environment, moderating translation when certain thresholds are reached.​

Therapeutic Frontiers Beyond Infectious Disease

A growing wave of clinical and preclinical research illustrates how design for longevity and control is going to be increasingly key to unlocking new indications. In oncology, mRNA is being used not only as a vaccine platform but also to drive sustained in situ production of cytokines,¹ checkpoint modulators,² and even full-length antibodies.³ In metabolic and rare diseases, mRNA offers a programmable route to protein replacement without permanent genomic alteration.^4,5 In regenerative medicine — including cardiac⁶ and bone⁷ repair — scientists hope to achieve carefully timed bursts of growth factor expression that mirror physiological healing windows.​

Looking Ahead: Longevity As A Co-Design Axis

The first wave of mRNA medicines demonstrated that transient expression could be safe, immunogenic, and scalable at a global level. The next wave will be defined by mastery over time – molecular messages engineered to persist just long enough to achieve therapeutic effect and then fade predictably.​

In this context, mRNA longevity is no longer a passive biophysical property but a deliberate design axis. The most successful “players” will likely treat mRNA design as a strategic asset rather than a technical afterthought, embedding it into discovery workflows, clinical planning, and commercial models from the outset. Every synthetic mRNA sequence represents more than mere functional innovation; it is a protectable intellectual property and a differentiator in an increasingly crowded landscape.

Realizing this potential will require formulation and mRNA sequence design to advance hand in hand. Future programs must be built around co-optimized mRNA–vehicle pairs, where the sequence (payload) and its carrier (vehicle) are finely tuned to deliver cell- and tissue-specific expression with appropriate durability. Those who master this interplay will redefine what mRNA therapeutics can achieve.

References:

1. Christian Hotz et al. Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models. Sci. Transl. Med.13,eabc7804(2021). DOI:10.1126/scitranslmed.abc7804
2. John D. Powderly et al. Phase 1/2 study of mRNA-4359 administered alone and in combination with immune checkpoint blockade in adult participants with advanced solid tumors. J Clin Oncol 41, TPS2676-TPS2676(2023). DOI:10.1200/JCO.2023.41.16_suppl.TPS2676
3. Christiane R. Stadler et al. Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6.Sci. Transl. Med.16,eadl2720(2024). DOI:10.1126/scitranslmed.adl2720
4. Yu H, Brewer E, Shields M, et al. Restoring ornithine transcarbamylase (OTC) activity in an OTC-deficient mouse model using LUNAR-OTC mRNA. Clin Transl Disc. 2022; 2 e33. https://doi.org/10.1002/ctd2.33
5. Koeberl, D., Schulze, A., Sondheimer, N. et al. Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia. Nature 628, 872–877 (2024). https://doi.org/10.1038/s41586-024-07266-7
6. Anttila V, Saraste A, Knuuti J, Hedman M, Jaakkola P, Laugwitz KL, Krane M, Jeppsson A, Sillanmäki S, Rosenmeier J, Zingmark P, Rudvik A, Garkaviy P, Watson C, Pangalos MN, Chien KR, Fritsche-Danielson R, Collén A, Gan LM. Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting. Mol Ther. 2023 Mar 1;31(3):866-874. doi: 10.1016/j.ymthe.2022.11.017. Epub 2022 Dec 17. PMID: 36528793; PMCID: PMC10014220.
7. Rodolfo E. De La Vega et al. Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2. Sci. Adv.8,eabl6242(2022). DOI:10.1126/sciadv.abl6242

About The Experts

Carol Tan‑Fujita, Ph.D., is the business and innovation manager at the Australia Centre for RNA Therapeutics in Cancer (ACRTC) and the RNA Innovation Foundry (RIF) at The University of Western Australia. With nearly a decade of experience driving strategic and operational R&D initiatives, she has shaped major biomedical programs, including the design of a national RNA therapeutics and manufacturing initiative in Singapore. Tan-Fujita specializes in building multidisciplinary partnerships and innovation pipelines that accelerate emerging technologies toward clinical and commercial translation. She holds a Ph.D. in biomedical science from the National University of Singapore.

Archa Fox, Ph.D., is director of the Australian Centre for RNA Therapeutics in Cancer (ACRTC) and the RNA Innovation Foundry (RIF), and a leading RNA biology professor at The University of Western Australia. She is internationally recognized for discovering RNA seeded paraspeckles and advancing their therapeutic potential. Her national leadership has helped shape Australia’s RNA biotechnology landscape, contributing to major investments in RNA manufacturing and innovation. Fox also serves on multiple national advisory groups, scientific boards, and steering committees, including appointment to Australia’s National Science and Technology Council. She holds a Ph.D. in biochemistry and molecular biology from the University of Sydney.