Engineered Nanoplatforms Targeting Activated Hepatic Stellate Cells for Liver Fibrosis Therapy via TGF‐β Axis Inhibition and Ferroptosis Induction

ABSTRACT Liver fibrosis and its terminal stage, cirrhosis, represent a major cause of morbidity and mortality related to hepatic pathologies. Activated hepatic stellate cells (aHSCs) are the principal drivers of fibrogenesis and therefore constitute key therapeutic targets. Lanifibranor, a pan‐peroxisome proliferator‐activated receptor agonist, has shown promising antifibrotic efficacy; however, its clinical application is limited by rapid systemic clearance and insufficient accumulation in fibrotic liver tissue. In this study, we report an aHSC‐targeted nanoplatform for lanifibranor delivery based on vitamin A‐functionalized two‐dimensional iron sulfide nanosheets (FeS‐V A @lanifibranor, FVL). Lanifibranor was electrostatically loaded onto vitamin A‐modified FeS nanosheets, enabling selective uptake by aHSCs and enhancing hepatic accumulation of lanifibranor. FVL significantly downregulated the expression of key fibrogenic markers and markedly reduced collagen accumulation. Mechanistically, the therapeutic efficacy of FVL arises from a dual‐action mechanism: inhibition of SMAD2/3 phosphorylation within the transforming growth factor‐β (TGF‐β) signaling pathway and induction of ferroptosis in aHSCs. In conclusion, this study provides an effective aHSC‐specific nanotherapeutic strategy for liver fibrosis treatment and highlights the translational potential of FVL nanoplatforms for targeted antifibrotic therapy.