Differences in the immunogenicity of engineered circular RNAs.

Circular RNAs (circRNAs) are single-stranded RNAs that are covalently closed and lack free ends. While relatively little is known about the roles of circRNAs in innate immunity, several studies suggest that endogenous circRNAs are immunosuppressive in nature. But whether engineered circRNAs produced exogenously and then delivered into cells are immunostimulatory has been a debated question in recent years. In this perspective, we review and compare the investigations on engineered circRNA immunogenicity. We discuss the possible factors that may alter the immunogenic potential of a circRNA, such as its generation, purification, primary sequence, secondary structure, and RNA modifications. We also suggest approaches for designing a circRNA with immunostimulatory or immune-evasive properties and recommend future areas for the field to investigate. A clear understanding of the immune effects from engineered circRNAs would offer insight into fundamental principles of how cells differentiate between self and non-self RNAs as well as provide a foundation for translating circRNAs into therapies.