While circRNA is often framed as a more stable, longer-lasting alternative to linear mRNA, its real-world advantages remain largely theoretical, and it is unclear whether greater molecular stability will translate into meaningful clinical gains.

In the past few years, mRNA vaccines have shifted from a laboratory concept to a fast and successful global health tool. Since their success during the COVID-19 pandemic, mRNA vaccines have expanded into cancer immunotherapy, respiratory vaccines and vaccines for infectious diseases like HIV and malaria. This expansion has sparked a new wave of interest in next-generation RNA technologies, including circular RNA (circRNA). CircRNAs are single-stranded, covalently closed RNA loops that lack 5′ or 3′ ends, making them highly stable against enzymatic degradation, unlike their linear RNA counterparts. Researchers are actively developing circRNA into vaccines to treat a variety of cancers and infectious diseases, but it is still unclear whether they will take the place of mRNA, or if they will even make it through clinical trials.

Originally thought to be by-products of erroneous splicing, circRNAs have been revealed by high-throughput sequencing to be highly evolutionarily conserved, physiologically functional, and prevalent in eukaryotic cells, with a half-life substantially longer than that of linear RNA. Scientists found evidence that they function as scaffolds, binding and regulating microRNAs and proteins, and help to facilitate protein–protein interactions. Within the last ten years, researchers have figured out how to precisely engineer circRNAs to produce protein in a sustained way within mammalian cells1, leading to the idea that they could be used as an alternative platform for vaccines — an idea that took off after mRNA vaccines set a new vaccine standard.

But cancer vaccines are where circRNAs could make a real clinical impact — not because the platform has proven superiority, but because the immunological demands of cancer align unusually well with what circRNA is theoretically suited to provide. Unlike infectious disease vaccines, which primarily rely on rapid, short-lived bursts of antibody production, effective cancer vaccines depend on sustained antigen presentation to drive robust cytotoxic T cell responses and overcome the immunosuppressive environment of tumors. In this context, circRNA’s resistance to degradation and potential for prolonged protein expression become particularly relevant. Extended antigen availability may improve T cell priming and strengthen immune memory, especially when combined with checkpoint inhibitors that release inhibitory brakes on the immune system. This is especially relevant for ‘cold’ tumors that do not naturally trigger strong immune responses.

Right now, researchers are trying to prove that circRNA does have these advantages in mouse models. Early studies have shown that circRNA can act as an adjuvant, activate immune responses and inhibit melanoma growth2. A study published last year showed that vaccines containing small circRNA showed longer shelf life and produced a stronger immune cell response in mice compared with vaccines with mRNA, larger circRNAs, or even mRNA containing modifications to enhance stability. The mice also appeared to tolerate higher doses of the small circRNA vaccine, with all vaccines eliciting dose-dependent responses over 180 days3. The small circRNA vaccine was also tested on several tumor types in mice in combinations with other immunotherapies, with promising results. Another group recently presented data that a circRNA vaccine increased tumor-related immune responses more than an mRNA vaccine in mouse models of lung cancer4, but it is not clear by how much.

Personalized neoantigen vaccines are another area where circRNA looks especially attractive by comparison to personalized mRNA vaccines — so far in mouse models. Neoantigen vaccines are designed around mutations unique to an individual’s tumor, and the aim is to train the immune system to recognize those highly specific ‘non-self’ targets that are highly specific to the tumor and less likely to be shared with normal tissue. CircRNA is modular, is relatively stable, and can potentially produce sustained antigen expression from very small amounts of input material, which may simplify formulation to produce highly customized constructs that could be changed relatively quickly depending on disease progression.

Early studies have found that a circRNA neoantigen vaccine combined with anti-PD-1 therapy improved tumor infiltration of CD8+ T cells in a mouse colon adenocarcinoma tumor model, reducing the immunosuppressive tumor microenvironment and inhibiting tumor growth3. Other studies have looked at hepatocellular carcinoma5 and melanoma models6, although there is no direct comparison to mRNA vaccines, and sample sizes are small in all cases. For infectious disease vaccination, circRNA’s appeal rests on the hypothesis that longer-lasting antigen expression could extend immune memory compared to the short-lived protein production typical of mRNA vaccines. In principle, the antigen’s sustained presence might improve antibody maturation and reinforce T and B cell memory, both of which would potentially translate into more durable protection or a reduced need for boosters. CircRNA vaccines produce potent antibody and T cell responses against SARS-CoV-2 and emerging variants in mice and non-human primates7,8. However, the reality is that mRNA vaccines already generate strong and durable immunity in many settings, and it is not yet clear that extending antigen expression necessarily improves outcomes, rather than simply prolonging stimulation. Unlike in cancer, where persistent antigen exposure may help overcome immune suppression within tumors, infectious disease vaccination already performs well under a ‘brief exposure, strong memory’ model.

With all this promise, it is somewhat surprising that nothing is currently moving through clinical trials. Early this year, Eli Lilly acquired Orna Therapeutics for $2.4 billion, gaining access to Orna’s circRNA and lipid nanoparticle-based therapies for autoimmune disease. Another biotech, Circuna, has a handful of circRNAs for vaccines and immunotherapies looking to reach phase 1 trials in the next two years. Otherwise, the field is quiet.

There may be a few reasons for this. First, the general funding landscape around mRNA and vaccines has decreased substantially over the past year in the United States. The main reason, though, may be that circRNA has not yet proven that it is a better option than linear RNAs, especially compared to stably modified versions, or self-amplifying RNAs9. When you already have a good vaccine, there is little incentive to change it.

It is not yet clear whether circRNA will become a second wave of RNA medicines or whether they will end up being just an alternative for specific, targeted applications. Like mRNA vaccines, circRNA has delivery challenges that need improvement, and it has not yet been shown that they can be produced at scale. The long-lasting nature of circRNA could also have unknown safety tradeoffs.

Biology has a long history of curing cancer in mice — only a fraction of therapies that work in mouse tumor models prove to be safe and effective in humans. CircRNA vaccines have promise, but whether that promise survives the transition from mice to humans will determine whether they are a footnote or the next era in vaccinology.