The emergence of mRNA-based vaccines and therapeutics has revolutionized medicine by enabling rapid development and versatile treatment options. However, one fundamental limitation has persisted: the inherent instability of messenger RNA molecules within the in vivo environment. Despite significant advances in delivery systems and chemical modifications, mRNA degradation remains a bottleneck that limits the duration and magnitude of protein expression, ultimately curbing therapeutic efficacy. The instability problem is compounded by the natural cellular processes that rapidly recognize and degrade foreign RNA, resulting in a transient protein expression window that for many applications falls short of clinical needs.
In an ambitious study, researchers boldly confronted this challenge by mining an enormous viral sequence database, encompassing nearly two hundred thousand sequences, in search of elements that confer exceptional stability and enhance translation. This meticulous screening effort led to the identification of eleven discrete RNA elements with a marked capacity to prolong mRNA half-life and simultaneously boost protein production. Viral genomes are a natural treasure trove of stability-augmenting sequences due to viruses’ evolutionary pressure to evade host defenses while maximizing replication, and leveraging these viral-derived elements represents a pioneering approach to RNA therapeutic design.
Delving into the mechanistic underpinnings, the study revealed that these newly identified stability elements exert their effects by recruiting the cellular enzyme TENT4. This enzyme is known to catalyze the extension of the poly(A) tail, a crucial half-life determinant for mRNA molecules. By enhancing polyadenylation, these elements effectively slow down the process of deadenylation, a key pathway leading to mRNA decay. The strategic recruitment of TENT4 thus emerges as a novel biological mechanism to shield therapeutic RNA from premature degradation, setting this approach apart from previous attempts that largely focused on chemical modifications or lipid nanoparticle optimization.
One of the critical barriers in mRNA technology is the compatibility of modified nucleosides, such as N¹-methylpseudouridine, which are introduced to reduce immune activation and improve translational capacity. Importantly, the study found that five of the eleven RNA stability elements were fully compatible with such base modifications. This compatibility is a monumental breakthrough, as it paves the way for durable yet immunologically inert mRNAs, overcoming a trade-off that has long hindered the clinical application of more durable RNA formats like circular or self-amplifying RNAs. Enhanced stability without immunogenic penalties promises broader therapeutic applicability across various diseases.
Among the identified elements, one dubbed A7 demonstrated extraordinary functional robustness across a range of experimental conditions, including diverse cell types, delivery approaches, modifications, and coding regions. This versatility signals that A7 can serve as a universal RNA stability enhancer, potentially standardizing mRNA therapeutic formulations and simplifying the manufacturing pipeline. The ability to maintain stability across such varied biological landscapes is exceedingly rare and underscores the high translational potential of this viral-derived sequence.
When comparing A7-containing linear mRNA to traditionally more stable but challenging-to-manufacture circular RNA, the results were striking. While circular RNAs generally boast extended in vivo persistence, their low translation efficiency and complex production have limited widespread adoption. Linear mRNAs equipped with the A7 element not only matched the durability of circular RNA but consistently achieved higher translation levels, thus combining the best features of both RNA design worlds. This represents a paradigm shift in RNA engineering strategies, suggesting that enhanced linear mRNA could effectively render circular RNA obsolete for many clinical scenarios.
Moreover, animal studies lent compelling in vivo validation to these findings. In mouse liver models, injection of A7-enhanced linear mRNA yielded protein expression levels that far surpassed those achieved with circular RNA constructs. Strikingly, protein synthesis was sustained for over two weeks—a timescale that significantly outperforms most current mRNA therapies. This durable expression window could translate into fewer dosing events for patients, improved therapeutic outcomes, and reduced healthcare costs, especially in chronic disease contexts.
The implications of these findings extend beyond vaccines to encompass a broad spectrum of mRNA therapeutics, including enzyme replacement, cancer immunotherapy, and gene editing. Longevity in mRNA expression facilitates more precise control of protein dosages over time, circumventing the peaks and troughs caused by rapid RNA degradation. Enhanced stability elements also minimize concerns about dosing frequency and may expand the repertoire of conditions addressable with mRNA technology, from genetic disorders needing sustained enzyme secretion to regenerative medicine applications requiring long-term protein availability.
Another significant advantage lies in the simplicity of manufacturing. Circular RNA and self-amplifying RNA platforms often involve complex synthesis or replication steps that can be cost-prohibitive and scale-limiting. Integrating stability elements like A7 into linear mRNA allows manufacturers to leverage existing streamlined production workflows, notably in vitro transcription methods, without introducing additional burdensome complexity. This ease of scalability positions such mRNAs well for rapid deployment during public health emergencies or mass vaccination campaigns.
The intersection of RNA chemistry, virology, and biotechnology highlighted in this work offers a testament to the power of interdisciplinary research. By embracing viral evolutionary innovations and harnessing enzymatic pathways such as TENT4-mediated polyadenylation, scientists have unlocked new potential to transform conventional mRNA therapeutics. The synthesis of these fields promises to accelerate development timelines and broaden the impact of RNA technologies, moving treatments from the laboratory bench to the bedside with unprecedented efficiency.
While this study focused on specific viral elements and modifications, it opens the door for further exploration into how viral genomes may house other RNA regulatory sequences with therapeutic value. Coupling bioinformatic mining with functional assays and mechanistic insight lays the groundwork for a new era of RNA design, where stability and efficacy are engineered at the sequence level rather than through trial-and-error chemical tweaks. These findings redefine what is achievable in mRNA performance and herald a future where stable, potent, and safe RNA medicines become the norm.
The authors note that ongoing research is anticipated to investigate these elements in other organs, disease models, and delivery vehicles, to fully delineate their potential and limitations. Questions regarding long-term safety, immunogenicity upon repeated dosing, and regulatory considerations remain to be definitively answered as the platform advances toward clinical translation. However, the foundational discovery of elements like A7 provides a solid basis on which to build next-generation mRNA therapeutics that are both highly effective and commercially viable.
In summary, this landmark study provides a blueprint for overcoming the longstanding challenge of mRNA instability by integrating viral sequence-derived RNA stability enhancers capable of recruiting TENT4 to extend poly(A) tails. The establishment of A7 as a potent, widely compatible element for durable mRNA expression redefines the field by bridging the gap between stability and high translation efficiency. These breakthroughs promise to fundamentally reshape mRNA therapeutic landscapes, enabling treatments with sustained protein production, reduced immunogenicity, and simpler manufacturing processes, likely influencing vaccine development, gene therapy, and beyond.
As mRNA technology continues its meteoric rise, embedding robustness and longevity into RNA constructs through biologically inspired design represents an evolutionary step with major clinical and commercial ramifications. This achievement underscores the evolving sophistication in RNA engineering and offers a hopeful horizon where the full promise of mRNA medicines can be realized—not as ephemeral agents but as durable, effective therapeutic tools for a vast array of medical challenges.
Subject of Research: RNA stability enhancers for base-modified mRNA therapeutics.
Article Title: RNA stability enhancers for durable base-modified mRNA therapeutics.
Article References:
Jung, SJ., Seo, J.J., Lee, S. et al. RNA stability enhancers for durable base-modified mRNA therapeutics. Nat Biotechnol (2025). https://doi.org/10.1038/s41587-025-02891-7
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41587-025-02891-7
Tags: boosting protein expression durationcellular processes in RNA degradationchemical modifications for mRNAenhancing therapeutic efficacy of mRNAimproving mRNA half-life and translationin vivo RNA stability solutionsinnovative mRNA delivery systemsmRNA stability enhancementovercoming mRNA degradation challengesRNA therapeutic design strategiesviral sequence database miningviral-derived RNA elements
