Circular RNA encoding relaxin-2 as a potential therapy for liver fibrosis

Circular RNAs (circRNAs) have recently emerged as a promising new drug modality with significant therapeutic potential due to their higher stability and lower immunogenicity. Here, we report the development of a circRNA encoding human relaxin-2 (cRLN2), a short peptide hormone with well-established therapeutic potential, to treat liver fibrosis in a mouse model. Compared to the modified linear mRNA, cRLN2 mediated stronger and more prolonged expression of relaxin <i>in vitro</i>. In addition, the nanoparticle-mediated delivery of cRLN2 achieved a sustained translation into active relaxin in healthy mice with low immunogenicity. In a mouse model of liver fibrosis, cRLN2 treatment significantly decreased hepatic stellate cell activation and consequently reduced collagen deposition in fibrotic mice, while the treatment by relaxin protein showed limited anti-fibrosis effects. Toxicity evaluation confirmed that cRLN2 exhibits excellent safety and tolerability in mice. Collectively, our findings demonstrate that cRLN2 can efficiently express therapeutic proteins <i>in vivo</i> and alleviate liver fibrosis without obvious toxic effects, highlighting the potential of circRNAs as a novel therapeutic platform to treat fibrotic diseases.