Dual-Phase Barrier-Penetrating Nanomedicine for Early Intervention on Hepatic Stellate Cells to Enhance Liver Fibrosis Treatment.

Inhibition of activated hepatic stellate cells (HSCs) is essential for treating fibrotic liver disease, while the capillarized hepatic sinusoidal barrier extremely hinders HSC-targeted drug delivery and early intervention. Herein, we developed a dual-phase barrier-penetrating nanomedicine (SFR-RA@lip) based on the coassembly of silibinin (SIL) and riociguat (RIO), with retinoic acid (RA) for HSCs targeting and a lipid shell to facilitate multipathway transcellular transport. In the initial phase, SFR-RA@lip exploits caveolin-mediated endocytosis and endoplasmic reticulum-Golgi apparatus trafficking to rapidly traverse liver sinusoidal endothelial cells (LSECs) and reach HSCs for an early intervention. Meanwhile, clathrin-mediated endocytosis facilitates the normalization of LSECs, restoring fenestrae through the NO-sGC-cGMP pathway activation. This fenestrae restoration facilitates a second-phase delivery, further enhancing the drug transport and accumulation in HSCs. In a thioacetamide-induced fibrotic liver model, SFR-RA@lip demonstrated significantly improved hepatic distribution and antifibrotic efficacy. This dual-phase nanosystem enhances trans-sinusoidal drug delivery and improves antifibrotic efficacy, offering a promising strategy for the treatment of liver fibrosis.