α-SMA/VCAM-1 Dual-Targeted Nanoplatform Improves Drug Release and Therapeutic Efficacy in Liver Fibrosis

Liver fibrosis is a progressive pathological condition characterized by hepatic stellate cell (HSC) activation and vascular endothelial dysfunction, where single-target therapies often fail to disrupt the pathological feedback loop between inflammation and extracellular matrix (ECM) deposition. In this study, we developed a dual-targeted nanocarrier system functionalized with α-smooth muscle actin (α-SMA) and vascular cell adhesion molecule-1 (VCAM-1) ligands to simultaneously inhibit activated HSCs and VCAM-1–expressing endothelial cells. Nanocarriers were prepared using a thin-film hydration and ultrasonic dispersion method, loaded with siRNA-HSP47, and characterized by dynamic light scattering, transmission electron microscopy, and HPLC. In vitro release assays demonstrated that dual-targeted nanocarriers achieved sustained release with a cumulative rate exceeding 80% at 72 h, significantly higher than single-target carriers (∼60%), and fitted well with the Higuchi diffusion model. In a CCl4-induced mouse liver fibrosis model (n = 48), in vivo fluorescence imaging revealed greater hepatic accumulation and prolonged retention time for dual-targeted nanocarriers, as described by a first-order elimination model. Histological staining and immunohistochemistry confirmed reduced collagen deposition and lower expression of α-SMA and TGF-β1 in the dual-targeted group, while serum ALT and AST levels were significantly improved (P < 0.05). These findings demonstrate that dual-targeted nanocarriers effectively disrupt the inflammation–fibrogenesis feedback loop by simultaneously modulating HSC activation and endothelial inflammation, offering sustained release, enhanced hepatic retention, and superior therapeutic efficacy. This strategy provides a promising platform for antifibrotic therapy and has potential for broader applications in other fibrosis-related diseases.