Beyond The Hype: How 2025's Successes & Realities Will Shape mRNA In 2026
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
There’s no denying that 2025 was a year fraught with challenges. Not only was the mRNA space faced with significant political and regulatory upheavals, but we were occasionally met with sobering data from programs across the entire advanced therapies space — several RNA programs included.
But in contrast to these deep valleys, 2025 was also marked by several incredible highs. As we showcased in part 1 of this multi-part Outlook series, our space has never been more dedicated to moving from prophylactic to therapeutic use cases, with more companies releasing preclinical data and entering the clinic. In 2025, Big Pharma crowned in vivo gene editing and in vivo CAR-T the “Belles of the Ball” by making high-profile acquisitions — several of which were based on preclinical data alone. (Hello again, 2020: We’ve sure missed your funding habits.) mRNA-based gene editing took over headlines with the celebratory news about Baby KJ and the partnerships that made it possible. And though manufacturing advancements are rarely front and center, we continued to see mRNA-specific manufacturing technologies and next-generation raw materials launched to improve RNA constructs and reduce COGS.
While I think it’s safe to say we would prefer to avoid experiencing a repeat of 2025, we can’t ignore how the events of this previous year will go on to influence our progress toward the next generation of therapeutic RNA development in 2026.
Here, in part two of this multi-part series, we hear from Melissa Bonner, CSO of nChroma Bio and Andy Geall, CDO of Replicate Biosciences, who call attention to several developments of the past year they’ve been watching and how they see these developments informing our conversations about and work with mRNA in 2026 and beyond.
Level-Setting Expectations for mRNA in Oncology and N-of-1 Models
For a field that has been in dire need of a therapeutic win, we did celebrate a major field-emboldening development in 2025. Baby KJ became the first patient to be treated with a personalized in vivo (mRNA-based) gene editing product. By May, Baby KJ had been treated with three doses of the experimental gene therapy, and, as of late November, the treatment continues to be a success.
As Bonner went on to qualify, this was a “really uplifting and positive story” for rare disease patients and the RNA space, reaffirming what numerous conversations throughout 2025 emphasized: Showing how mRNA can therapeutically benefit patients and their caretakers will be a key ingredient in changing mRNA’s narrative for the better.
However, the Baby KJ story, as well as our ongoing discussions in the personalized oncology realm, both underscore an important takeaway for us as we progress into 2026: We need to remain level-headed. My conversation about mRNA in oncology at RNA Leaders USA 2025 was a beautiful introduction as to why we must, first and foremost, level-set expectations as we strive to tackle solid tumors with mRNA. Though we’d love to see mRNA singlehandedly take on solid tumors, the data we currently have for mRNA is in the adjuvant setting, emphasizing its current strengths as part of an overall regimen rather than as a single agent.
Likewise, though Baby KJ’s story was noteworthy in a lot of ways, one of the hallmarks was our ability to move industry-sized mountains to make it a reality. Though there have been numerous conversations and articles published since about how to make this development model a more widespread reality, there remain significant conversations that need to be had at an increasing frequency, particularly around the economics of such a model.
“We have to keep in mind that this drug was approved for administration, not for the commercial market,” Bonner pointed out. Not only does the n-of-1 model come with a drastically different risk-benefit ratio, but this was not a traditional conversation involving payers and reimbursement models, nor was it accompanied/impacted by typical biotech funding constraints.
“Without a more transparent discussion around the resources and costs that went into this type of development model, it’s going to be extremely challenging to answer to what extent such a model is possible on a broader scale and how it can be operationalized,” she added.
These types of discussions continue to grow more pressing. Beyond Baby KJ, we also saw an n-of-1 success in the AAV gene therapy space via Nationwide Children’s Hospital in 2025, as well as the FDA approval of Waskyra in Wiskott-Aldrich syndrome. Not only was the latter the first ex vivo gene therapy approved for this rare disease, but the therapy was developed by an Italian nonprofit — the first nonprofit to receive an FDA nod.
Given these successes, Bonner posed two valuable questions which clearly indicate how important these conversations should be as we enter 2026: “1., How do we scale this model to enable more breakthrough treatments for ultra rare indications? And 2., How does this model ultimately fit within our ecosystem? For example, does this live in the academic/nonprofit realm where reimbursement may be less of an issue?”
Manufacturing Advancements & Their Longer-Term Impacts
Achieving a sustainable RNA therapeutics industry also hinges upon us making manufacturing advancements to improve product quality and COGS and to broaden global access to vaccines and therapeutics. Fortunately, as Geall outlined for us, we’ve seen growth in many important areas over the past year, both from a capacity and a capability standpoint.
If we home in specifically on capacity, “There are great opportunities emerging outside of the U.S.,” Geall admitted when I asked him which manufacturing developments stood out most in 2025. “We’re starting to see infrastructure being built in the developing world as part of various initiatives, as well as advancing capabilities in the U.K., Singapore, and Australia. Governments have figured out that they need to create access, and one way to do this is through building local facilities.” Partnerships are equally valuable — Replicate’s latest collaboration announcement with Brazil’s Instituto Butantan being a fantastic example.
That’s not to say there isn’t capacity in the U.S. today; in fact, as Geall admitted, there’s too much capacity, thanks to funding challenges brought about by political and regulatory uncertainty. Without funding, companies don’t have the money to manufacture their drugs, a trend that is leaving larger CDMOs to prioritize development in alternative modalities and challenging smaller RNA-specific development partners. Likewise, as a speaker at a previous event also pointed out, this lack of funding has also been impacting the technologies space, a trend that could stymie growth of the enabling infrastructure in the U.S.
Though we’re certainly feeling pressure today in the U.S., Geall emphasized that progress continues to be made slowly but surely in the supply chain and with manufacturing technologies. Together, these combined efforts are reducing manufacturing times and costs and improving product quality. For example, in upstream processing/drug substance production, the arrival of synthetic DNA (namely for linear mRNA production) shaves roughly six months off development timelines, given we no longer need a master cell bank to produce our plasmids. Likewise, the gravitation away from wild-type T7 to engineered T7 polymerases — for example fusion T7/capping enzymes — are showing meaningful improvements in the reduction of dsRNA.
We’ve also begun to see innovation on the bioreactor front, with an increasing number of technology companies exploring flow chemistry for drug substance production. These are relatively small-scale technologies at present, and as such, are not a fit for high dose commercial scale mRNA products. But they are “lighting up [Geall’s] radar” for commercial scale production of next-gen saRNA drug substance, the enhanced expression of which translates into smaller dose sizes/commercial scale batch sizes overall. These technologies are also boasting an improvement in quality — particularly for more complex saRNAs that typically run into integrity issues as the constructs get larger. “Integrity is not a problem with flow chemistry-produced material,” Geall said. “We can now think about making 16kb, 18kb, maybe even 20kb RNAs.”
Thanks to the work we’re doing upstream to produce higher quality drug substances with fewer residual impurities, conversations are starting to shift around what our downstream processes could ultimately look like. For one, if we look strictly at the technologies, downstream production is becoming much more fit-for-purpose, with more competing microfluidic technologies coming to market for RNA-LNP formulation. Likewise, though we’ve previously had to rely on membranes designed for the purification of proteins, Geall points to the arrival of membranes designed specifically for isolating and purifying RNA-LNPs.
Perhaps most notable, however, are the benefits that the combined upstream and downstream advancements promise the field in the year ahead. As Geall concluded, “The space is doing a lot more optimization upstream with raw materials to lower residual dsRNA, which ultimately opens the door to a simpler, more streamlined downstream process.”
Miss part 1? Check it out here: