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 in vitro. 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 in vivo and alleviate liver fibrosis without obvious toxic effects, highlighting the potential of circRNAs as a novel therapeutic platform to treat fibrotic diseases.