Circular RNA: The Next Frontier for RNA Therapeutics?

mRNA medicines have been transformative, especially for vaccines, but their structure limits how long they can act in the body. Traditional mRNA is linear, meaning it has two ends that are quickly degraded by enzymes once inside cells. This makes the molecule short-lived and leads to only a brief burst of protein production. For applications that need sustained or precisely controlled expression, such as chronic diseases, this short activity window can be a challenge.

Delivery is also a hurdle, as mRNA medicines are traditionally delivered by lipid nanoparticles that naturally accumulate in the liver, leaving other organs and cell types harder to reach.

Circular RNA, or circRNA, is a closed-loop form of RNA that lacks free ends. Because of this structure, it is much more stable inside cells and resists degradation. Sail Biomedicines engineered a version that we call eRNA therapeutics that support extended, controlled protein production. The circular format allows us to “smooth out” expression over several days rather than seeing the sharp spike and drop typical of mRNA. This longer expression window helps maintain steady protein levels and can improve safety and function for complex proteins that need time to fold properly. In short, eRNA therapeutics combine durability with precision, giving scientists a new tool to match the timing of protein expression to the biology of a disease.

We’ve made encouraging progress in two key areas. In autoimmune disease, Sail has shown that eRNA constructs can be used to program a patient’s own T cells in vivo to act like CAR T cells, without the need for cell collection or complex manufacturing. In preclinical models, this approach led to deep depletion of B cells in the blood, lymph nodes and bone marrow, supporting the potential to reset the immune system in diseases, such as lupus.

We’ve also demonstrated that eRNA medicines can drive strong, lasting immune responses in vaccine models. In malaria studies funded by the Gates Foundation, eRNA vaccine candidates produced antibody levels up to 24 times higher than protein-based vaccines, and these responses remained elevated for 10 weeks. Together, these findings point to eRNA’s potential to power a broad range of RNA medicines, from vaccines to treatments for chronic conditions.

Most lipid nanoparticles used today are naturally taken up by the liver. This “liver sink” means that much of an injected dose never reaches its intended target. For many diseases, we need to deliver RNA to other organs or to specific cell types, such as immune cells, without affecting the liver. Another challenge is achieving efficient entry into target cells and ensuring that the RNA escapes the endosome, the small compartment that can trap it after uptake. It is critical to get all these steps right to ensure potency, safety and consistency across species.

Sail’s targeted nanoparticle (TNP) platform is designed to deliver eRNA constructs precisely where they are needed. We use biodegradable nanoparticles that can be “programmed” with specific targeting ligands to recognize and enter chosen cell types, such as CD4 and CD8 T cells. In preclinical studies, these TNPs achieved up to 80 percent delivery to T cells in non-human primates, with minimal uptake in the liver.

AI plays an important role in making this possible. We use AI and computational models to analyze thousands of nanoparticle formulations and biodistribution datasets. These models help predict how changes in particle composition, size or surface chemistry will affect delivery, allowing us to design new particles much more efficiently. Targeting ligand design and TNP incorporation are also critical to efficient delivery, where we have observed a dramatic increase in the efficiency and specificity of eRNA delivery. The result is a system in which delivery can be tuned as easily as the RNA itself, expanding what’s possible for RNA medicines.

The field is moving beyond vaccines into therapeutics for chronic and complex diseases. As new technologies like eRNA therapeutics and targeted delivery mature, we’ll see RNA used to produce therapeutic proteins, antibodies, and even transient cell therapies directly inside the body. RNA medicines will become more programmable and more specific, guided by AI-driven design and data from high-throughput testing. The next decade will be about accessibility and scale, turning today’s specialized, hospital-based treatments into off-the-shelf therapies that can reach far more patients.