Retinol-guided liposomal platform for targeted pirfenidone delivery in hepatic fibrosis

Liver fibrosis is a major contributor to global mortality due to its progressive disruption of hepatic architecture and function, and it remains a critical unmet medical need. Hepatic stellate cells (HSCs) are considered a key therapeutic target owing to their central role in fibrosis progression, primarily mediated through the TGF-β1/Smad2/3 signaling pathway. Pirfenidone (PFD), a clinically approved broad-spectrum antifibrotic agent, shows potential for repurposing in liver fibrosis therapy. However, its clinical translation is limited by poor aqueous solubility and a lack of cellular targeting specificity. To address these limitations, we developed a vitamin A-conjugated liposomal delivery system (P@GB-Lipo-VA) to enhance the liver-specific accumulation of PFD. In vitro studies demonstrated that P@GB-Lipo-VA significantly increased cellular uptake in TGF-β1-stimulated LX-2 cells and reduced oxidative stress. In a bile duct ligation (BDL)-induced mouse model of liver fibrosis, P@GB-Lipo-VA effectively alleviated collagen deposition, improved liver function, and suppressed activation of the TGF-β1/Smad signaling pathway. These findings support P@GB-Lipo-VA as a promising targeted nanotherapeutic platform for enhancing the efficacy and safety of PFD in the treatment of liver fibrosis.