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

TL;DR

A new circular RNA therapy encoding relaxin-2 was developed to treat liver fibrosis in mice, showing better results than traditional protein treatments.

Contribution

The study introduces a novel circRNA-based therapy for liver fibrosis with superior efficacy and safety compared to protein drugs.

Findings

cRLN2 mediated stronger and more prolonged relaxin expression compared to linear mRNA in vitro.

Nanoparticle-delivered cRLN2 reduced liver fibrosis in mice with low immunogenicity and no toxicity.

cRLN2 outperformed relaxin protein in reducing hepatic stellate cell activation and collagen deposition.

Abstract

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.

Liver delivery of circRNA-LNP enables sustained and safe expression of human relaxin-2, achieving potent antifibrotic activity under low immunogenicity and excellent tolerability, with efficacy superior to recombinant protein drugs. These findings support circRNAs as a promising platform for protein replacement treatments.

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