Engineering circular RNAs for efficient protein translation

Circular RNAs (circRNAs) are a class of RNA with multiple functions, including the ability to be translated. The intrinsic stability of circRNAs, due to their structure, confers them advantages over linear RNAs; therefore, circRNA-based drugs have recently received increasing attention. However, the inefficiency of their cap-independent translation and the difficulties in the large-scale production of long circRNAs negatively impact on their use in therapy. Some efforts have been done to solve these issues related to circRNA adoption, but, to date, circRNA translation still relies on long IRESs (600-800) and chemical group addition. In this study, we identified a 63-nt element able to drive circRNA translation comparably to the most commonly used IRESs. This element includes a 13-nt sequence previously reported to enhance linear RNA translation and a 50-nt segment of the UTR of the endogenously translated circRNA circZNF609. Notably, this element combines a comparable IRES-like efficiency to a considerably shorter length, expanding the landscape of ORFs potentially suitable for being translated from circRNAs and enhancing their potential as therapeutic agents in therapy.