FAPi‐Mediated siRNA Lipid Nanoparticles for the Treatment of Liver Fibrosis

Liver fibrosis lacks effective therapies largely due to the inability of conventional lipid nanoparticles (LNPs) to target activated hepatic stellate cells (HSCs), the primary drivers of fibrotic progression. Here, we developed a fibroblast activation protein inhibitor (FAPi)-modified LNP encapsulating heat shock protein 47 (HSP47) siRNA (FAPi-LNP/siHSP47) to target activated HSCs. FAPi-LNP/siHSP47 exhibited enhanced HSC targeting, efficient HSP47 silencing, reduced alpha-smooth muscle actin (α-SMA) expression, and marked attenuation of collagen deposition in vivo. Pharmacokinetic and protein corona analyses revealed that DSPE-PEG-based LNPs displayed prolonged circulation and increased area under the curve (AUC) compared with DMG-PEG formulations, while FAPi modification further enhanced AUC and reduced adsorption of complement protein C3 and apolipoprotein E (ApoE), thereby decreasing hepatocyte uptake. Importantly, acute toxicity evaluation demonstrated favorable in vivo biocompatibility without hematological, inflammatory, or histopathological abnormalities. Collectively, FAPi modification enabled LNPs to specifically target activated HSCs, providing a safe and effective treatment for liver fibrosis and presenting a new strategy for directing LNPs to cells beyond hepatocytes.