RNA's comeback tour

For decades, scientists dreamed about the seemingly limitless therapeutic potential of RNA. Part of what made RNA so compelling was its versatility. Across its various forms, RNA could target previously undruggable disease drivers, instruct cells to produce therapeutic proteins, silence harmful mutations, rewrite faulty RNA transcripts before they were translated into dysfunctional proteins, or train the immune system to fight disease.

But while the science was attractive on the lab bench, it was hampered by RNA’s inherent fragility, inefficient delivery into cells, and a lack of clinical proof that its challenges could be overcome.

The COVID-19 pandemic became the field’s long-awaited proving ground. Seemingly overnight, messenger RNA (mRNA) — an RNA subtype that carries a gene’s protein-building instructions to the cell’s machinery — became the defining biotechnology story of the decade. mRNA vaccines reached billions of people, demonstrating the technology’s speed and scalability on a level no laboratory result could match. The field surged. Investment flooded in.

Then the moment passed. Interest in pandemic vaccines waned, and the funding followed. At the same time, mRNA vaccines became caught in American political crossfire, culminating in HHS Secretary Robert F. Kennedy Jr. announcing a “coordinated wind-down” of mRNA vaccine development under BARDA, terminating roughly $500 million in research contracts.¹ Policy headwinds and public skepticism in pharma’s largest market gave global investors pause. Pharma companies reevaluated their pipelines.

Some questioned whether RNA’s chart-topping debut had been a one-hit wonder.

“For people working in the field, RNA has certainly not disappeared,” says John Cooke, MD, Ph.D., medical director of the RNA Therapeutics Program at the Houston Methodist Research Institute. Cooke says he spent much of the pandemic addressing misconceptions about mRNA vaccines. “It’s been frustrating to watch it go from being the fair-haired child that saved the world, to the word that nobody says when they’re writing a grant.”

Convinced of RNA’s potential beyond COVID, Cooke founded the Society for RNA Therapeutics in 2023 to accelerate RNA medicine through research, standards development, regulatory collaboration, and advocacy for broad patient access.

Erik Wiklund, Ph.D., CEO of Circio and co-discoverer of circular RNA (circRNA), has been on a similar ride. “It’s really been a roller coaster for RNA, up and down, over the past 25 years,” says Wiklund. “You had this tremendous success with the COVID vaccines...and now mRNA has become evil cousin that no one wants anything to do with, unfortunately.”

But RNA is not one thing, and it never was. Robert Bell, Ph.D., chief scientific officer of Ascidian Therapeutics, notes that the field is often “lumped into a single polarizing bucket.” “What people sometimes overlook,” he says, “is that most RNA therapeutics are designed to address the underlying biology driving a disease. When you can intervene at that level, you have the potential to deliver radical efficacy in patients.”

The headlines may have stopped singing the praises of mRNA vaccines, but the broader RNA story is far from over. Large pharmaceutical companies are investing in the next generation of cell and gene therapies, where RNA technologies — from RNA editing to circRNA to trans-splicing — are opening new possibilities. The emerging tune is not one of a technology in decline, but of a field evolving toward therapies that could be safer, more durable and more accessible.

RNA is having more moments

Contrary to the notion that the pandemic was RNA’s moment, Cooke says the field has never held more promise now that molecular and synthetic biology tools have finally caught up with decades of research.

“It’s a defining moment because 50 years of work in lipid nanoparticle delivery has given us better ways to get RNA into cells and allow it to do its job. There have also been developments in manufacturing that have made it easier to generate the drug product, as well as advances in regulatory understanding of RNA,” says Cooke. “All of this progress has brought us to a point where we now have software that we can use to generate an almost endless variety of drugs and vaccines for people.”

Cooke’s team at Houston Methodist Hospital recently developed and administered the first personalized mRNA cancer vaccine designed to prevent recurrence of osteosarcoma, an aggressive type of bone cancer. The treatment leveraged existing studies of similar methods that Cooke hopes will eventually lead to a personalized neoantigen mRNA vaccine for triple-negative breast cancer.

For many, the current moment represents the payoff of decades of RNA research. Ascidian Therapeutics believes it also represents a new beginning — one where RNA medicines move beyond replacing or delivering genetic instructions to directly correcting disease-causing defects.

Less than two years after its public launch in October 2022, Ascidian was the first to advance an RNA exon editor into clinical development after the FDA authorized its ACDN-01 program for Stargardt disease. While most RNA therapies either silence a gene or deliver a functional copy of a missing protein, Ascidian’s approach reconstructs a functional gene product by intercepting RNA splicing itself — redirecting the cell’s own splicing machinery to incorporate healthy replacement exons in place of mutated ones, without touching the underlying DNA.

Prior attempts at this process, known as trans-splicing, were hampered by low efficiency or lack of translation in preclinical models.² Bell says advances in molecular biology, next-generation sequencing and bioinformatics, paired with a deeper understanding of mechanisms controlling RNA splicing, have triggered a reemergence of interest in therapeutic RNA exon editing.

“The concept of using RNA trans-splicing for therapeutic purposes has been around for some time, but our understanding of splicing biology and how to engineer it is far more advanced than it was twenty years ago,” says Bell. “It’s really just the tip of the iceberg.”

Call it a comeback, a defining moment, or the start of a new era: Big pharma has made its position clear, pouring billions into RNA through partnerships and acquisitions.

In June 2025, AbbVie struck a potential $2.1 billion deal to acquire Capstan Therapeutics, betting on the company’s targeted lipid nanoparticle (LNP) platform for in vivo cell engineering.³ Four months later, Bristol Myers Squibb acquired Orbital Therapeutics for $1.5 billion, gaining its circRNA platform and lead in vivo CAR-T candidate.⁴ The following month, Novartis announced its $12 billion acquisition of Avidity Biosciences,⁵ one of the year’s largest biotech deals, underscoring the premium pharma companies are willing to pay for technologies that deliver RNA to previously inaccessible tissues.

Ascidian has also attracted major pharmaceutical interest. In 2024, Roche agreed to pay $42 million upfront with up to $1.8 billion in milestones in a development and licensing deal focused on neurological targets, while Lilly followed in 2026 with a partnership worth up to $1.9 billion to develop RNA exon-editing therapies for inherited kidney diseases.

“At a high level, Roche and Lilly are helping us extend the platform into indications and geographies that a small company simply couldn’t tackle alone,” says Bell. “If we can develop robust RNA exon editors for these indications, these partnerships will help ensure they reach patients who need them most. That’s a key piece of RNA’s revolution.”

With scientific advances accelerating and billions in pharma investment flowing into the field, RNA appears poised for not one defining moment, but many.

RNA’s in vivo era

If you’re looking to showcase RNA’s versatility beyond vaccines, in vivo CAR-T is arguably the hottest stage on which to do so.

In vivo approaches could offer a much-needed fix for the long timelines and complex manufacturing and supply chain infrastructures that are hindering access to FDA-approved ex vivo CAR-T cell therapies. In vivo CAR-Ts also have the benefit of bypassing the harsh chemotherapy pre-conditioning step needed for ex vivo therapies.

While some in vivo platforms use viral vectors, like lentivirus or adeno-associated virus, that permanently rewrite a cell’s DNA, other approaches take a different path, using LNPs that skip viral vectors altogether and let RNA act as the therapeutic payload.

“Current CAR-Ts are so expensive. But by using lipid nanoparticles to deliver mRNA, you can reprogram T-cells directly inside the body, and you’d potentially have something an order of magnitude less expensive,” says Cooke.

The growing interest in this area has been reflected in a wave of high-profile deals. In the past 18 months, major industry players AbbVie, BMS, Eli Lilly and Johnson & Johnson have committed roughly $6.9 billion (with J&J holding a further option to buy Sail outright for up to $2.58 billion) on tie-ups involving engineering cells inside the body using LNP-delivered RNA.^3,4,6,7

In the LNP-mRNA approach, the RNA acts as a temporary blueprint for CAR protein production in the cell’s cytoplasm. Because it never becomes DNA or integrates into the genome, CAR expression is transient: the protein fades as the RNA naturally degrades rather than becoming a permanent feature of the cell. As was the case with the mRNA COVID vaccines, the transient nature of RNA is an advantage in some instances.

“One of the things we’re doing at Methodist right now is to generate CAR-T cells against pathogenic B-cells that are causing autoimmune disease. The transient attribute of RNA can be a good thing when you’re working with a therapeutic product that you want to be active for only a short period of time. We don’t want CAR-T cells that are going to go on killing B-cells,” explains Cooke.

However, that transience also has drawbacks in settings where reprogrammed cells must persist and self-renew, creating a durability tradeoff for mRNA-based in vivo CAR-T therapies.

“First generation mRNA-based approaches are promising, but the issue is the expression window is very short — only one or two days — which may limit their efficacy and applicability,” says Wiklund.

Prior to founding Circio, Wiklund, together with Circio co-founder and CTO Thomas Hansen, Ph.D., published the discovery and characterization of the first thoroughly studied endogenous human circRNA. What he initially thought to be “strange-acting RNA” in 2011⁸ has now become what many companies are betting on as the future of RNA therapeutics.

Whereas linear RNA is a strand with two distinct, open ends (a 5’ cap and a 3’ poly-A tail), circRNA is a covalently closed loop with no free ends. Natural circRNAs have been discovered in a variety of tissues including in the brain, eyes and heart. The increased stability of engineered circRNAs has triggered substantial interest among researchers and pharma companies. Wiklund estimates that between 2021 and 2024, circRNA companies attracted approximately 40% of venture capital funding directed toward RNA-related technologies.⁹

CircRNA offers one fix to mRNA-based approaches without changing the delivery model at all. Swapped into the same one-time LNP dose in place of linear mRNA, its closed-loop structure resists the enzymes that degrade linear RNA, stretching the expression window to roughly seven to 10 days — several times longer, though still a finite dose that eventually gets used up.

Circio’s own circVec platform takes a different route. Rather than deliver finished RNA, a DNA construct delivered by a nonviral synthetic DNA vector directs the cell to continuously produce and circularize fresh RNA on its own. Because the cell keeps transcribing and circularizing RNA on an ongoing basis rather than receiving one finite dose, expression can run longer than any single-dose RNA therapeutic. Using the circVec platform, Circio has reported up to six months of expression in lymphocytes in vivo on a single dose.

Circio is now testing, in a new evaluation partnership with LNP specialist Acuitas Therapeutics and well as other delivery companies, whether circVec’s RNA can also be packaged into a one-time LNP dose. By pairing extended expression with targeted delivery, the partners hope to develop a novel in vivo CAR-T therapy with superior durability for cancer and certain autoimmune diseases.

RNA on the gene therapy stage

While in vivo CAR-T has captured much of the spotlight, RNA therapeutics could ultimately have a much broader setlist, extending to diseases that current gene replacement and editing technologies cannot readily address.

Conventional gene replacement — adding a functional copy of a gene to compensate for a defective or missing one — has transformed the treatment of some genetic diseases. One of the best-known examples, Novartis’ blockbuster Zolgensma, uses an AAV vector to deliver a healthy copy of the gene responsible for spinal muscular atrophy. But gene replacement is not a universal solution.

For starters, AAV vectors can carry only a limited amount of genetic cargo. Many disease-causing genes, like the one behind Duchenne muscular dystrophy, are simply too large to fit intact inside a single vector. In addition, the high doses often required to achieve a therapeutic effect can trigger serious immune-mediated toxicities.

Gene editing has offered a different path forward. The first approved CRISPR therapies, which correct disease by cutting or rewriting a patient’s DNA, have validated gene editing as a clinical reality. Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy demonstrated that precisely modifying a patient’s own stem cells can deliver durable benefit in inherited blood disorders. Yet significant challenges remain, including delivery barriers inside the body, the risk of unintended off-target edits and the high cost of treatments.

Some of these limitations are what drew Robert Bell to Ascidian after leading research across several gene therapy programs in Pfizer’s rare disease research unit. “For me, this opportunity really highlighted a potential chance to address disease mechanisms that are difficult to reach with existing approaches,” he says.

Instead of replacing an entire gene or permanently altering DNA, Ascidian’s platform replaces only the disease-causing exons at the RNA level. Because the editing payload is much smaller, it can fit inside AAV and other delivery systems. The approach removes mutated exons and inserts healthy ones in a single reaction, restoring normal protein production without permanently altering the underlying genome or introducing foreign enzymes.

This can also offer an important safety advantage.

“If you introduce an unintended change in DNA — a deletion, insertion or mutation outside the intended target — every RNA molecule produced from that DNA region now carries that change,” says Bell. “That’s why understanding and managing off-target effects at the DNA level is so important.”

Earlier this year, Ascidian launched the phase 1/2 STELLAR trial of ACDN-01 in Stargardt disease and presented its first-in-human safety data at ASGCT 2026. But the company’s ambitions extend far beyond inherited retinal disorders. Ascidian’s partnership with Roche focuses on difficult-to-treat neurological diseases, while its collaboration with Lilly targets genetic kidney disorders — indications that often fall beyond the reach of conventional gene therapies.

“We started in the eye, but from the earliest days of Ascidian we believed the platform had potential across a number of genetic and even complex disorders,” Bell says. “The vision was always broader, but we wanted to start in a place where we could reduce technical risk and focus on evaluating this novel RNA exon-editing platform in the clinic.”

For Ascidian, Stargardt disease was a logical place to start. The disease represents a significant unmet need, ophthalmology has a well-established gene therapy delivery framework, and retinal diseases offer safety and efficacy endpoints that can be monitored relatively easily. The rare inherited eye disorder is caused by mutations in the ABCA4 gene, which drives progressive retinal degeneration and vision loss. Like Duchenne’s dystrophin gene, ABCA4 is too large to fit into a single AAV vector, and with more than 1,200 known disease-causing mutations and no dominant hotspot, mutation-specific base editing is not a practical solution.

Other RNA companies are pursuing a different goal: overcoming the dosing and toxicity limitations that have challenged conventional AAV gene therapies. Those concerns were thrust into the spotlight this year after two Duchenne muscular dystrophy patients died from acute liver failure following treatment with Sarepta Therapeutics’ gene therapy, Elevidys.¹⁰

“You typically need really large doses of AAV to get a therapeutic effect, especially when delivered systemically — and those doses lead to high, often fatal, toxicity,” says Wiklund. “They also complicate manufacturing, driving up costs.”

Circio believes circRNA may offer a solution. Because circRNA is structurally more stable and can drive higher levels of protein expression, circRNA-expressing AAV gene therapies may require significantly less viral vector material to achieve the same clinical benefit as a conventional mRNA-expressing AAV. In theory, generating more protein from each AAV genome could enable developers to lower doses while addressing both toxicity and manufacturing costs. According to Circio, its circVec platform increases protein expression per vector copy by up to 50-fold in preclinical heart and eye models.

Together, companies like Ascidian and Circio illustrate how RNA is evolving beyond a single technology. Whether by correcting genetic instructions at the RNA level or improving the efficiency of gene delivery, these approaches aim to tackle diseases and manufacturing challenges that conventional gene replacement and editing technologies have yet to overcome.

Behind the music

The road to stardom is rarely smooth. Traditional linear mRNA manufacturing was once complex, labor-intensive, and dependent on expensive raw materials. Although the COVID-19 vaccine response accelerated manufacturing innovation and drove down costs, a new generation of RNA therapeutics is introducing a fresh set of challenges.

Circular RNA, for example, has the potential to simplify manufacturing. Because it does not require 5’ caps, poly(A) tails, or modified nucleotides, circRNA eliminates several production steps while retaining the ability to drive protein expression. But the field remains nascent, and companies are still working to establish scalable, GMP-compliant manufacturing processes.

“It’s a new modality, so it just takes time to figure out,” says Wiklund. “It was the same with antibodies in the beginning: expensive, cumbersome — and only a few specialists could do it. Now it’s completely mainstream.”

One challenge is circularization itself. Self-splicing methods do not convert all linear precursor RNA into finished circles, reducing yields and creating impurities that must be removed during purification.

“The challenge for some companies using self-splicing strategies has been achieving both sufficiently high yields and the purity required for GMP manufacturing,” says Wiklund. “That’s taken longer than expected because you can’t simply borrow existing mRNA purification processes.”

Circio is attempting to bypass these bottlenecks entirely. Rather than producing synthetic circRNA in a manufacturing plant, its circVec platform delivers a DNA construct via AAV, allowing the circularization to occur inside the patient’s own cells after transcription. Because cells continuously produce fresh RNA, the approach avoids many of the yield and purification constraints associated with ex vivo manufacturing.

Manufacturing is only part of the challenge. Unlike linear mRNA, which benefited from years of COVID-era process optimization, next-gen RNA modalities lack a standardized playbook. No single synthesis strategy has yet achieved the ideal balance of efficiency, purity, scalability and regulatory robustness. And because technologies such as RNA exon editing and circRNA have not yet produced an approved therapy, neither manufacturers nor regulators have an established CMC framework to follow.

For Cooke, that uncertainty was one of the driving forces behind the creation of the Society for RNA Therapeutics.

“The society allows people to come together, share best practices, exchange ideas and improve how we’re developing these products,” he says. “It’s a new field, and there’s a lot to learn. The society is here to accelerate that learning process.”

While approved RNA medicines have largely consisted of vaccines, siRNAs, and antisense oligonucleotides, emerging technologies are increasingly converging with the cell and gene therapy world. It’s a fortuitous crossover because in many ways, RNA therapeutics are encountering the same manufacturing and regulatory growing pains that cell and gene therapies faced a decade earlier.

“Cell and gene therapy has spent the last 15 years solving manufacturing challenges that can equally be applied to RNA,” says Cooke. “Many of the same questions — particularly around personalized medicines — will require new manufacturing and regulatory approaches if these therapies are going to become a reality.”

Changing the public tune

In the U.S., public sentiment toward RNA has proved fickle. mRNA vaccines went from pandemic hero to political lightning rod in just a few years, often with little regard for the underlying science.

“I don’t think it’s entirely on the authorities. I think the companies involved fumbled the communication, too. There were a lot of misconceptions, and they didn’t do a good job explaining the technology, rationale and deep underlying science and safety data,” says Wiklund.

Bell agrees that as the industry pursues increasingly diverse RNA-based medicines, communication will be just as important as scientific progress.

“I think much of the responsibility falls to drug developers and scientists to be precise and accurate, but also in a way that can be understood by non-scientifically trained individuals,” he says. “The merits of any RNA therapeutic should be evaluated independently, based on its mechanism, its potential impact on patients, and its safety profile.”

Setbacks involving next-generation RNA platforms have also shaped perceptions of the field. In 2022, biotech startup Laronde faced intense scrutiny after an internal investigation revealed problems with key preclinical data supporting its lead candidate, which relied on the company’s proprietary ‘endless RNA’ technology. Missing raw data and unsuccessful attempts to reproduce findings generated by the company’s top scientist fueled speculation that the results had been fabricated, although Laronde maintained that the discrepancies stemmed from flawed assays and poor recordkeeping.¹¹ The controversy ultimately underscored concerns about scientific rigor and data integrity — not the broader promise of RNA therapeutics.

But the tide may have just turned for Laronde. In 2023, Laronde merged with Senda Biosciences to form Sail Biomedicines, combining endless RNA with programmable nanoparticle technologies to develop a pipeline of in vivo cell therapies. Those technologies recently caught the attention of Johnson & Johnson, which agreed to pay $785 million upfront in a partnership deal and secured an option to acquire the company for an additional $2.58 billion.⁷

Wiklund is hopeful that the next generation of RNA medicines will ultimately reshape the public narrative.

“If in vivo CAR-T delivers positive clinical results and brings that therapeutic strategy to many more patients in a simpler and cheaper way, hopefully that can create a positive story around mRNA and turn public sentiment,” he says.

RNA’s reputation may have been forged by a pandemic, but its future will likely be determined by something far less dramatic: the steady accumulation of clinical data, regulatory milestones and, ultimately, patient benefit. The standing ovation that accompanied mRNA vaccines has long since quieted, but scientists believe the field’s most important work is only beginning. In the end, RNA’s legacy won’t be defined by a single breakout performance, but by the depth and durability of its catalog. 

References

 1. U.S. Department of Health and Human Services. (2025, August 5). HHS winds down mRNA development under BARDA. [press release]
 2. Doi, A. et al. (2024, Aug). RNA exon editing: Splicing the way to treat human diseases. Mol Ther Nucleic Acids. 35(3). 102311.
 3. AbbVie to acquire Capstan Therapeutics. (2025, June 30). AbbVie. [press release]
 4. Bristol Myers Squibb strengthens and diversifies cell therapy portfolio with acquisition of Orbital Therapeutics. (2025, Oct). Bristol Myers Squibb. [press release]
 5. Novartis agrees to acquire Avidity Biosciences, innovator in RNA therapeutics. (2025, Oct). Novartis. [press release]
 6. Lilly to acquire Orna Therapeutics to advance cell therapies. (2026, Feb). Eli Lilly. [press release]
 7. Johnson & Johnson announces collaboration with Sail Biomedicines to advance in vivo CAR-T programs. (2026, July 29). Johnson & Johnson. [press release]
 8. Hansen, T. et al. (2011, Sept). miRNA‐dependent gene silencing involving Ago2‐mediated cleavage of a circular antisense RNA. EMBO J. 30, 4414-4422.
 9. Wiklund, E. (2024, May). Commentary: The therapeutic potential of circular RNA. MedNouse.
10. Roche, Sarepta halt Elevidys use following second patient death. (2025, June). Cell & Gene Therapy Review.
11. DeAngelis, A. and Cross, R. (2023, June 12). The inside story of how data integrity issues roiled a biotech seen as ‘Moderna 2.0. STAT and The Boston Globe.