Unlocking the potential of engineered circular RNA therapeutics

Linear RNA-based therapeutics such as messenger RNAs, antisense oligonucleotides, and small interfering RNAs are limited by susceptibility to nuclease degradation, reduced in vivo stability, and potential immunogenicity, which hinder their broader clinical applications. Circular RNAs (circRNAs) represent a type of single-stranded RNA molecule characterized by a covalently closed circular structure formed through back-splicing. Due to their resistance to exonuclease-mediated degradation and relatively decreased innate immune activation, circRNAs represent a versatile RNA tool capable of long-lasting protein expression. Endogenous circRNAs regulate gene expression via miRNA sponging and protein interactions and, in select cases, support cap-independent translation. Dysregulated circRNAs have been implicated in cancer, metabolic disease, and inflammation. Recent technological advances have enabled efficient engineering of synthetic circRNAs, incorporating optimized components for enhanced circularization, purification, and translational performance. In addition, progress in delivery platforms, including lipid nanoparticles, viral vectors, and biomimetic carriers, has expanded the therapeutic potential of circRNAs across oncology, infectious diseases, and immune modulation. Here, we summarize the biological features and therapeutic applications of circRNAs, highlight strategies to overcome manufacturing and delivery challenges, and discuss the future opportunities for unlocking the clinical potential of engineered circRNA therapeutics.