Cellular Adaptive Component-Mediated Targeting of Chylomicron-Mimic Nanoemulsion to Hepatic Stellate Cells for Liver Fibrosis

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.