Orna Therapeutics is a biotechnology company building a drug platform around circular RNA, a form of genetic messenger that loops back on itself in a closed ring rather than running in a straight line like the mRNA used in COVID-19 vaccines. That structural difference turns out to have real pharmacological consequences, chiefly greater stability inside cells and prolonged protein production. Orna’s bet is that these properties can unlock therapies that linear mRNA struggles to deliver, from injectable CAR-T cell treatments that skip the complex manufacturing of today’s cell therapies to vaccines that produce antigen for days longer than conventional shots.
What Makes Circular RNA Different From Linear mRNA
Standard messenger RNA is a single strand with two exposed ends, called the 5′ and 3′ ends. Cells are full of enzymes called exonucleases whose job is to chew RNA from those exposed tips. That is why unmodified mRNA degrades quickly once it enters a cell. Circular RNA sidesteps this problem entirely: its ends are joined in a covalent bond, forming a continuous loop with no free tips for exonucleases to grab onto.1PubMed Central. Circular RNA: An emerging frontier in RNA therapeutic targets, RNA therapeutics, and mRNA vaccines The result is a molecule with a substantially longer half-life than its linear counterpart.2Molecular Therapy – Nucleic Acids. Recent research progress on circular RNAs: Biogenesis, properties, functions, and therapeutic potential
Circular RNAs are not just a lab invention. Cells naturally produce thousands of them through a process called back-splicing, where a downstream exon loops back and joins an upstream one. For a long time, scientists dismissed these molecules as splicing errors. That changed over the past decade as researchers discovered that endogenous circular RNAs play real biological roles, including acting as sponges that soak up regulatory microRNAs. The molecules are present in human blood cells at higher stability than linear mRNAs, which is part of why they attracted attention as potential biomarkers for disease.3PubMed Central. Circular RNA, A Molecule with Potential Chemistry and Applications in RNA-based Cancer Therapeutics
Even circular RNA is not immortal, though. A 2025 study identified an enzyme called DIS3 that degrades circular RNAs through an internal-cutting mechanism rather than chewing from the ends. Depleting DIS3 in cells caused more than 60 percent of circular RNAs to accumulate, revealing that cells do have a way to clear them. Circular RNAs containing stretches rich in the nucleotide uracil were especially vulnerable to DIS3, a detail that matters for therapeutic design because engineers can potentially tune the sequence to control how long a circular RNA persists.4PubMed. Degradation of circular RNA by the ribonuclease DIS3
Teaching a Circle to Make Protein
Stability alone is not useful if the circular RNA cannot tell a ribosome to start reading it. Normal mRNA has a chemical cap on its 5′ end that ribosomes recognize as a “start here” signal. A circle has no 5′ end, so it needs another way to recruit the translation machinery. The solution comes from structures called internal ribosome entry sites, or IRES elements, which are RNA sequences that fold into shapes ribosomes can latch onto without a cap.
IRES elements were originally discovered in viruses. Some viruses hijack host ribosomes by embedding these structured landing pads in their own RNA, and researchers have borrowed the trick for synthetic circular RNA. Early work found that the IRES from Coxsackievirus B3 (CVB3) drove about 50 percent more protein production than the more commonly used IRES from encephalomyocarditis virus (EMCV) in human cells. Adding an internal polyA sequence downstream of the IRES further boosted output, possibly by reducing physical crowding around the ribosome-binding site.5Nature Communications. Engineering circular RNA for potent and stable translation in eukaryotic cells
More recent efforts have pushed this further. One approach used a high-throughput screen to test thousands of candidate sequences and identified over 17,000 RNA elements, both natural and synthetic, capable of directing circular RNA translation in human cells.6PubMed Central. Structured elements drive extensive circular RNA translation Another team engineered synthetic IRES variants by inserting an aptamer that recruits translation initiation factors directly; variants with the aptamer placed in specific loops of the IRES structure showed significantly improved translation over the wild-type version.7Nature Biotechnology. Engineering circular RNA for enhanced protein production A separate strategy tested dual-IRES designs, placing a second IRES downstream of the protein-coding region to support the first one. Screening pairwise combinations of viral IRES elements yielded configurations that markedly increased protein expression compared with single-IRES constructs.8PubMed Central. Enhancing Circular RNA Translation Efficiency Through Dual Internal Ribosome Entry Sites
This work matters for Orna and the broader field because the level of protein a circular RNA produces is one of the main practical limitations. If you can get a circle to express protein at levels competitive with chemically modified linear mRNA, the stability advantage translates directly into longer-lasting therapeutic effects.
How Synthetic Circular RNA Is Made
Making a closed RNA loop in a test tube is trickier than making a straight strand. The dominant method borrows from nature: a system called permuted intron-exon (PIE) splicing, which uses a catalytic intron (a self-splicing RNA enzyme) from a bacteriophage or bacterium. You insert the sequence you want circularized between two halves of the intron, add the cofactors GTP and magnesium, and the intron catalyzes its own removal while joining the two ends of your payload into a circle.9Theranostics. Developing an enhanced chimeric permuted intron-exon system for circular RNA therapeutics
A newer twist on this approach, called PIET, splits the reaction into two separate RNA molecules that react in trans. The 5′ half-intron and an intermediate are generated in independent reactions, then mixed together. Researchers found that splicing still occurred under these conditions and that GTP was no longer required as a cofactor, simplifying the process.10PubMed Central. Self-splicing RNA circularization facilitated by intact group I and II introns
An alternative to enzymatic splicing is direct ligation, where an enzyme like T4 RNA ligase physically joins the ends of a linear precursor. This method avoids leaving behind any intron-derived sequence fragments in the final circular product, which has implications for immunogenicity that we will get to shortly.
The Immunogenicity Debate
One of the most contested questions in the circular RNA field is whether synthetic circular RNA triggers the innate immune system. The answer, frustratingly, appears to be “it depends on how you make it.” A landmark 2017 study showed that transfecting in-vitro-generated circular RNA into mammalian cells triggered a strong innate immune response through the sensor RIG-I, and that this sensing depended on the intron used to produce the circle. When a human intron was used instead of a foreign one, the immune activation disappeared, suggesting that cells can distinguish “self” circular RNA from “foreign” circles based on their biogenesis history.11PubMed Central. Sensing Self and Foreign Circular RNAs by Intron Identity
That finding was challenged by subsequent work suggesting the immune response was actually caused by contaminating linear RNA left over from the circularization reaction, not by the circular RNA itself. Other researchers pushed back, showing that even after rigorous purification by gel extraction or chromatography, circles produced by intron-directed splicing still provoked immune responses. A key 2022 study compared three different production methods and found that circles made by PIE splicing (using group I introns) were immunogenic, while circles made by direct ligation were not. The difference was attributed to remnant sequences left behind by the autocatalytic splicing rather than to leftover linear contaminants.12Journal of Molecular Cell Biology. Differences in the immunogenicity of engineered circular RNAs
Separately, researchers who produced artificial circular RNA sponges by in vitro transcription and ligation reported that their purified circles did not trigger cellular RNA sensors or downstream immune signaling.13Molecular Therapy Nucleic Acids. Low Immunogenicity of Artificial Circular RNA Sponges Produced by In Vitro Transcription and Ligation The practical takeaway is that the production and purification method chosen for circular RNA therapeutics can make or break the immunogenicity profile, and companies like Orna have strong incentives to optimize their proprietary circularization and cleanup protocols to minimize unwanted immune activation while preserving any immune stimulation that might be desirable in a vaccine context.
Delivering Circular RNA With Lipid Nanoparticles
Circular RNA on its own cannot cross cell membranes efficiently. Like linear mRNA, it needs a delivery vehicle. Lipid nanoparticles, the fatty droplets that delivered the Pfizer and Moderna COVID vaccines, are the leading option. Orna uses what it calls immunotropic LNPs, lipid formulations designed to reach immune cells rather than defaulting to the liver, which is where standard LNPs tend to end up.
The liver-tropism problem is a real bottleneck for any RNA therapy aimed at immune cells. Standard LNPs accumulate in hepatocytes because they pick up a blood protein called ApoE that directs them to liver receptors. One approach to redirect delivery uses antibody-conjugated LNPs that target surface markers on T cells. In preclinical work, these targeted LNPs achieved potent T-cell transfection and, when loaded with CAR-encoding mRNA, drove antibody- and dose-dependent CAR expression along with depletion of up to 90 percent of target B cells.14PubMed. In Vivo mRNA CAR T Cell Engineering via Targeted Ionizable Lipid Nanoparticles with Extrahepatic Tropism
Optimized LNP formulations for circular RNA are an active area of research. One group developed a platform that, upon intramuscular injection in mice, showed substantial accumulation in draining lymph nodes and strong activation of dendritic cells, the immune cells responsible for kick-starting adaptive immunity. This is exactly the behavior you want for a vaccine delivery system.15PubMed Central. Circular RNA lipid nanoparticle vaccine against SARS-CoV-2 Another study used systematic formulation screening and identified an LNP composition that significantly enhanced circular RNA expression compared to commercially available alternatives, enabling the programming of stem cells into functional endothelial cells and liver-like cells.16Advanced Functional Materials. Optimized Lipid Nanoparticles Delivery Enables Efficient Circular RNA‐Mediated Forward Programming and Lineage Specification of Induced Pluripotent Stem Cells
Orna’s panCAR Platform
Orna’s most prominent therapeutic program is panCAR, an approach to chimeric antigen receptor (CAR) therapy that sidesteps the laborious process of extracting a patient’s T cells, engineering them in a lab, and infusing them back. Instead, panCAR delivers CAR-encoding circular RNA inside immunotropic LNPs directly into the bloodstream. The LNPs transfect immune effector cells in the body, turning them into CAR-expressing cells on the spot.
The company has disclosed preclinical data for an anti-BCMA panCAR targeting multiple myeloma. In vitro, high surface expression of the CAR was observed on both human and cynomolgus monkey immune cells in a dose-dependent fashion and was maintained for at least 72 hours.17Blood. In Vivo pan CAR therapy utilizing circular RNA for treatment of multiple myeloma Because the circular RNA is eventually degraded, CAR expression is transient. That transience is a feature, not a bug: if the therapy causes problems, the effect fades on its own. And because the treatment is an off-the-shelf injectable rather than a personalized cell product, it can be re-dosed as needed.
Orna is also developing an anti-CD19 panCAR aimed at autoimmune diseases, evaluated in humanized mouse models with intravenous injection.18Blood. In Vivo pan CAR therapy utilizing circular RNA for treatment of autoimmune diseases The rationale mirrors the recent excitement around using CD19-targeting CAR-T cells for conditions like lupus and myasthenia gravis, where depleting autoreactive B cells can reset the immune system. An injectable, re-dosable version would dramatically lower the barrier to access if it works in humans.
Circular RNA in Cancer Immunotherapy and Wound Healing
Beyond Orna’s specific programs, the circular RNA field has been exploring several therapeutic avenues that illustrate the platform’s versatility. In cancer immunotherapy, researchers have used circular RNA to encode cytokines, the signaling proteins that rally the immune system against tumors. One team showed that injecting circular RNA encoding a mix of cytokines directly into tumors reshaped both local and systemic anti-tumor immune responses in mice and improved the effectiveness of anti-PD-1 checkpoint therapy.19Molecular Therapy Nucleic Acids. Engineered circular RNA for advanced cancer immunotherapy Separately, a single intratumoral injection of LNPs loaded with circular RNA encoding IL-12 triggered marked tumor regression in a lung cancer model, with large increases in immune cell infiltration at the tumor site.20PubMed. Tumor-Tailored Ionizable Lipid Nanoparticles Facilitate IL-12 Circular RNA Delivery for Enhanced Lung Cancer Immunotherapy
The prolonged expression profile of circular RNA is particularly appealing for wound healing, where you want sustained delivery of growth factors without repeated dosing. A study using circular RNA encoding VEGF-A, a protein that promotes blood vessel growth, demonstrated strong expression at the wound site for about a week followed by a gradual decline over the second week. In a diabetic wound model, this sustained VEGF-A release accelerated healing, pointing toward potential applications for conditions like diabetic foot ulcers where poor circulation makes wound repair especially difficult.21PubMed. A single dose of VEGF-A circular RNA sustains in situ long-term expression of protein to accelerate diabetic wound healing
How Circular RNA Compares to Linear mRNA in Practice
The COVID vaccines proved that linear mRNA works. So what does circular RNA actually add? In head-to-head comparisons, circular RNA has consistently shown longer-lasting protein expression. One direct comparison found that circular RNA reached the highest expression levels and sustained expression roughly a day longer than both unmodified and chemically modified linear RNA.22Molecular Therapy: Nucleic Acids. Comparative evaluation of circular and linear RNA platforms: expression dynamics, immune responses, and safety A one-day difference may not sound dramatic, but for applications where you need a sustained protein depot, like local cytokine delivery to a tumor or growth factor expression in a wound, that extra persistence compounds into a meaningful advantage.
A recent review framed the comparison with a useful nuance: circular RNA plausibly offers the most added value in settings like single-dose local protein depots and durable antigen expression for certain vaccine strategies. In other settings, the advantages may diminish compared with optimized linear mRNA or self-amplifying RNA, which can replicate itself inside cells to amplify expression through a different mechanism.23PubMed Central. Circular RNA therapeutics: a new class of long-acting RNA medicines for oncology, immunology, and rare diseases The honest picture is that circular RNA is not categorically superior to linear mRNA. It is a complementary tool with specific strengths in durability and stability that matter more for some applications than others.
Manufacturing and Cold Chain Challenges
One of the practical headaches of mRNA medicines, as the world learned during the pandemic, is that they often need to be stored at ultra-cold temperatures. Circular RNA faces the same challenge when packaged in lipid nanoparticles, and researchers are working on solutions. One group developed a lyophilized (freeze-dried) circular RNA vaccine encapsulated in LNPs that maintained its stability and lymph-node-targeting properties after reconstitution, offering a path toward room-temperature or refrigerator-stable products.24PubMed Central. Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses
Purification is another manufacturing challenge. After the circularization reaction, the product is a mix of the desired circular RNA, unreacted linear precursor, and other byproducts. Those contaminants need to be removed, both to maximize potency and to avoid the immunogenicity issues discussed earlier. The standard industrial approach has been HPLC, which is expensive and hard to scale. A recent study demonstrated that affinity chromatography using oligo(dT) columns achieved high yield and purity comparable to HPLC, and the resulting product could be successfully lyophilized using novel ionizable lipids. LNPs formulated with one of the new lipids sustained protein expression over a 14-day period, outperforming the lipid used in Moderna’s COVID vaccine.25PubMed Central. A Complete Approach for circRNA Therapeutics from Purification to Lyophilized Delivery Using Novel Ionizable Lipids
Circular RNA Beyond Protein Expression
Most of the attention on Orna and its competitors focuses on using circular RNA to encode proteins. But one of the more striking recent demonstrations of circular RNA therapy works through an entirely different mechanism. A team used circular ADAR-recruiting RNAs (circ-arRNAs) not to produce a new protein but to edit existing RNA. Their target was Duchenne muscular dystrophy (DMD), a devastating genetic disease caused by mutations that disrupt the reading frame of the dystrophin gene. The circular RNAs recruited the cell’s own RNA-editing enzyme, ADAR, to modify splicing signals and skip the mutated exon, restoring dystrophin production from the patient’s own gene.
In nonhuman primates carrying DMD mutations, a single dose achieved durable dystrophin restoration and sustained motor improvement for at least a year and a half without provoking an immune response against the restored protein. A first-in-human study then showed that a single dose of the therapy, delivered via adeno-associated virus, produced safe, dose-dependent exon skipping in three patients, with measurable gains in motor and heart-lung function.26Cell Press. Long-term reversal of Duchenne muscular dystrophy via circular arRNA-guided exon skipping in monkeys and humans This is not Orna’s work, but it illustrates how the circular RNA format is enabling therapeutic strategies that go beyond simply being a more durable mRNA. The closed-loop structure provides stability for applications where a therapeutic RNA needs to persist in cells for weeks or months, as it does when correcting a genetic defect rather than producing a transient burst of protein.
That breadth of application space, from transient injectable CAR-T therapy to long-lived gene correction, is part of what makes the circular RNA platform interesting to watch. Orna’s own programs are still preclinical, and the gap between impressive mouse data and a working human medicine is famously wide. But the underlying biology, an RNA molecule that resists degradation, produces protein without a cap, and can be re-dosed without the manufacturing complexity of cell therapy, gives the technology a set of practical advantages that linear mRNA does not easily replicate. Whether those advantages survive contact with human clinical trials will determine whether circular RNA becomes the next major RNA medicine platform or remains an elegant idea that worked better in the lab than in the clinic.