The Therapeutic Potential of Circular RNA

Among the many types of RNA being evaluated for therapeutic applications is circular RNA. Although this RNA type is less tested than mRNA, it may hold potential advantages over mRNA.

Notably, Mass General Brigham (MGB)'s Gene and Cell Therapy Institute (GCTI), which was established several years ago with the intent of helping some of the innovative preclinical research in cell and gene therapy make the leap to clinical trials, is currently working on the application of circular RNA to therapeutic purposes. CGTLive® spoke with Robert Alexander Wesselhoeft, PhD, the director of RNA Therapeutics at GCTI, at the American Society of Gene & Cell Therapy (ASGCT) 28th Annual Meeting, held May 13 to 17, 2025, to about the potential advantages, applications, and challenges of using circular RNA in medicine.

Robert Alexander Wesselhoeft, PhD: The GCTI is a new institute within MGB aimed at filling the translational gap between early stage research and clinical trials. What we're hoping to do at the GCTI is basically provide resources to investigators within MGB (but also with partners outside of MGB) to support the translation of those early ideas through manufacturing support, expertise, and clinical and regulatory support.

In addition to some of the more general capabilities that GCTI has around gene and cell therapy, we're also trying to get into some of the cutting edge technologies that have emerged in the space in the last few years, and one of those is circular RNA. Like the mRNA coronavirus vaccines that were recently approved by the FDA, circular RNA has the ability to basically encode any protein you want. You can formulate it into lipid nanoparticles and send it to tissues of interest in the body in order to produce a specific gene product (protein) in those tissues. Circular RNA has lots of advantages over mRNA, including the price of manufacturing and the stability of the molecule, which allows it to really open doors in terms of therapeutics that really aren't available to mRNA because of its short half-life. We are aiming to become one of the leaders in the circular RNA space, at least academically—driving forward innovation on circular RNA and then eventually translation into medicines.

The nice thing about circular RNA is that it's a platform technology so it can be applied to many, many different things—I would say more things than mRNA because of its stability. I've seen people using it for vaccines, which is, I would say, a relatively easier application of the technology because you only need very low doses for a high level of efficacy. But people are also looking into gene editing with circular RNA for rare genetic diseases, and in some cases, immunotherapy, especially in vivo chimeric antigen receptor T-cell therapy. There are a number of different companies working on that and a variety of other transient applications, where you want protein expression for maybe a week or 2 weeks, but not for the rest of time.

Circular RNA is a pretty new technology still. It's a lot newer than mRNA, and it's taken probably a few decades now to work out all of the challenges with mRNA. Circular RNA has benefited from a lot of that work because of the similarity and the structure of the molecule, but key challenges include large scale manufacturing of circular RNA—I would say it's almost solved at this point, but it hasn't really been proven in a clinical setting, as mRNA has—and so manufacturing at large scales, as well as optimization of the sequence elements to further improve the protein expression from the molecule beyond where it currently stands.