Circular RNA as emerging precision therapeutics: from RNA regulation to peptide translation

Abstract Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs characterized by covalently closed-loop structure. Although initially regarded as splicing byproducts, circRNAs are now recognized as essential regulators of gene and protein expression and play important roles in various human diseases. In recent years, growing evidence has indicated that a subset of circRNAs can be translated through cap-independent mechanisms to produce bioactive peptides or proteins. These findings expand the functional scope of circRNAs and offer new opportunities for RNA therapy. This review summarizes recent advances in circRNA biology, with an emphasis on their potential in diagnosis and treatment. We also review the therapeutic strategies targeting circRNAs at both the RNA and protein levels and the delivery systems that support circRNA-directed therapies. After we discuss how circRNA therapeutics may be integrated into precision medicine, we further highlight the current clinical progress and key challenges for advancing circRNA-based therapies toward clinical application.