A ’stealth’ gene delivery system targeting hepatic stellate cells for the treatment of liver fibrosis

Liver fibrosis is a progressive condition characterized by excessive accumulation of extracellular matrix components, which impairs liver function and can lead to cirrhosis or hepatocellular carcinoma. In this study, we designed a multifunctional poly(amidoamine) dendrimer-based gene delivery system (VA/CLU/COL-P@mp) to target activated hepatic stellate cells (aHSCs) and mitgate liver fibrosis. This platform leverages clusterin (CLU) for Kupffer cell evasion, collagenase I (COL) to enhance nanoparticle penetration through fibrotic ECM, and vitamin A for targeted binding to retinol-binding protein (RBP) receptors on aHSCs. The system codelivers miR-29a and relaxin plasmid (pRLN), with miR-29a shown to upregulate PPAR-γ and sensitize aHSCs to relaxin. The treatment with VA/CLU/COL-P@mp significantly reduced collagen deposition, improved liver function biomarkers, and restored normal liver architecture, compared to controls, as confirmed by histological analysis. These findings demonstrate the therapeutic potential of targeted gene delivery for reversing liver fibrosis and restoring hepatic function.