Abstract

Hepatic stellate cell (HSC) activation and macrophage dysregulation drive liver fibrosis progression, characterized by pathological endoplasmic reticulum stress (ERS) hyperactivation and peroxisome proliferator-activated receptor pathway (PPAR-γ) suppression in both cell types. Targeting ERS and PPAR-γ represents a promising antifibrotic strategy. Despite nanotechnology's potential for targeted fibrosis therapy, the liver’s complex anatomy challenges precise endoplasmic reticulum drug delivery. Here, we propose a cell-adaptive component (CAC)-based strategy using a chylomicron-like lipid nanoemulsion with liver tropism. This nanoemulsion achieves organ-level liver accumulation, cellular-level synchronous targeting via macrophage phagocytosis and retinol-mediated HSC uptake, and subcellular-level endoplasmic reticulum enrichment through phosphatidylinositol-enhanced caveolin-mediated endocytic trafficking, enabling endoplasmic reticulum enrichment and subsequent PPAR-γ nuclear translocation. Alone, the nanoemulsion alleviated early fibrosis by suppressing the ERS of HSC; combined with PPAR-γ agonists, it reversed advanced fibrosis by disrupting HSC–macrophage crosstalk. This approach provides a stage-adaptable, precise-targeting platform for liver fibrosis therapy.