Oral self-assembly nanoemulsion drives <i>in vivo</i> hepatic stellate cell-targeting drug delivery in liver fibrosis

Hepatic fibrosis is a chronic liver disease that requires long-term treatment and is characterized by the excessive accumulation of extracellular matrix (ECM), which is produced primarily by activated hepatic stellate cells (aHSCs). Oral medication represents a non-invasive and crucial strategy for prolonged therapy. However, achieving targeted drug delivery to aHSCs through oral administration remains a significant challenge because of the susceptibility of nanoparticles to structural disruption during intestinal transit. To address this, an oral vitamin A (VA)-functionalized self-nanoemulsifying drug delivery system (termed VA-SNEDDS) was fabricated for the precise delivery of morin (MOR) to aHSCs for the treatment of liver fibrosis. After oral administration, the designed VA-SNEDDS successfully translocated across the intestinal epithelium while maintaining the structural integrity of the nanoemulsion, entered the systemic circulation via the lymphatic pathway, and ultimately accumulated in aHSCs within fibrotic livers through VA- and retinol-binding protein receptor-mediated binding. In a carbon tetrachloride (CCl4)-induced fibrotic rat model, treatment with MOR-loaded VA-SNEDDS significantly attenuated liver fibrosis by reducing ECM deposition, hydroxyproline content, and transforming growth factor-β1 (TGF-β1) expression while concurrently restoring liver function. This study provides an orally administrable aHSCs-targeted platform with high translocation efficiency and indicates potential for this strategy in the treatment of liver fibrosis.