Abstract
Although microRNAs (miRNAs) binding to messenger RNAs (mRNAs) generally results in mRNA degradation and reduced protein expression, their interaction with the internal ribosome entry sites (IRES) of certain RNA viruses enhances viral amplification and expression. In this study, we utilized the natural hepatitis C cirus (HCV) 5' UTR region, which contains miR-122 binding sites, as the IRES of circular RNA (circRNAs) constructs. These circRNAs allowed inducible expression of downstream genes with high specificity in response to both exogenous and endogenous miR-122. Substituting the miR-122 binding sites with those for other miRNAs also resulted in the translational activation of circRNAs by their respective miRNAs in transfected cells. Furthermore, mouse models administered intravenously with lipid nanoparticle-formulated circRNAs containing miRNA binding sites (circRNA-LNP) exhibited higher expression in targeted tissues compared to those with mutated binding sites. Our research introduces a novel strategy for tissue-specific regulation of circRNA expression, potentially broadening the therapeutic applications of circRNAs and paving the way for more precise and effective treatments in gene therapy.