Circular RNAs (circRNAs) are a unique class of single-stranded RNA molecules that are covalently closed and lack 5′ and 3′ ends. They were first discovered in eukaryotic cells >30 years ago, but technical limitations hindered the characterization of circRNAs until the 2010s. Recent advances in high-throughput RNA sequencing (RNA-seq), coupled with circRNA enrichment using RNase R treatment and new bioinformatic tools, have led to the discovery of a large number of circRNAs in various eukaryotic organisms, including mammals, insects, nematodes, plants, and yeast. Most circRNAs are generated through back-splicing of pre-mRNAs. Several studies showed that the expression levels of some circRNAs are significantly higher than that of their corresponding linear RNAs (Jeck et al., 2013; Salzman et al., 2013), indicating that circRNA biogenesis is tightly regulated. Although the mechanisms of circRNA biogenesis are still unclear, there are three regulatory models: (i) the RNA secondary structure mediates back-splicing through complementary sequences, such as Alu repeat sequences; (ii) RNA-binding proteins facilitate back-splicing, such as QKI; and (iii) the splicing intermediate lariat drives back-splicing.

Some studies showed that most circRNAs are non-functional (Xu and,Zhang, 2021), while several other studies showed that circRNAs can function as miRNA sponges, protein sponges, protein scaffolds, or translation templates. In addition, circRNAs are much more stable than linear RNAs in cells, making them a promising platform for RNA therapy. Here, we discuss the biological functions and therapeutic potential of circRNAs.