Abstract

Liver fibrosis represents a critical intermediate stage in the progression of chronic liver diseases toward cirrhosis. Conventional therapeutic strategies remain limited by insufficient efficacy, notable side effects, or narrow applicability, making the effective reversal of fibrosis a persistent clinical challenge. Although gene silencing technologies offer a promising therapeutic avenue, their clinical translation is hampered by poor delivery efficiency, instability in vivo, and lack of tissue specificity. To address these issues, we developed a lactobionic acid‐modified aminated glycogen (Lac‐AGly) nanoparticle system for the targeted delivery of connective tissue growth factor (CTGF) targeting small interfering RNA (siRNA). By utilizing natural glycogen as a biodegradable backbone, a degree of amination of 51.2% conferred efficient siRNA binding capacity, while Lac modification enabled selective recognition of hepatocyte-expressed asialoglycoprotein receptors. The resulting Lac-AGly/siCTGF nanocomplexes exhibited a uniform spherical morphology with an average particle size of 247.2 ± 8.8 nm and a zeta potential of 28.5 ± 3.8 mV. In vivo studies demonstrated that Lac-AGly/siCTGF significantly attenuated liver fibrosis, evidenced by a reduction in the collagen-positive area from 14.3% to 3.1%. Collectively, the Lac‐AGly/siCTGF nanoparticle system integrated biocompatibility, serum stability, and active hepatic targeting into a single platform, significantly improving siRNA delivery efficiency and gene‐silencing efficacy while maintaining favorable biosafety. This work provided a novel and translatable strategy for precise molecular intervention in liver fibrosis.