Liver-Targeting Nanoparticles GA-MSe@AR Treat NAFLD Through Dual Lipid-Lowering and Antioxidant Efficacy.

Background and Purpose: Non-alcoholic fatty liver disease (NAFLD) is prevalent worldwide and lacks effective treatments. Arctiin (AR), a natural product, has shown promise for NAFLD therapy, due to its antioxidant, anti-inflammatory, and inhibition adipogenesis properties. However, its therapeutic efficacy is hindered by low water solubility, poor bioavailability, and inadequate liver targeting. In this study, selenium-based antioxidant nanoparticles were developed to load and deliver AR to the liver for synergistic AR and selenium effective treatment of NAFLD. Methods: The therapeutic potential of AR was analyzed by network pharmacology. GA-MSe@AR was synthesized by encapsulating AR within galactose-modified mesoporous selenium nanoparticles (GA-MSe) for liver-specific targeting. The nanoparticle size, chemical structure, and elemental composition were explored. The toxicity, cellular uptake, lysosomal escape, and AR release efficiency of GA-MSe@AR were investigated by in vitro experiments. The liver targeting ability of GA-MSe@AR was evaluated through live imaging. The lipid-lowering and antioxidant activities of GA-MSe@AR were assessed in both in vitro and in vivo NAFLD models. Additionally, its effects on inflammation and pancreatic function were analyzed in vivo. Results: Network pharmacology analysis revealed AR may against NAFLD through regulating metabolism, inflammation, and oxidative stress. GA-MSe@AR exhibited low toxicity, efficient cellular uptake, remarkable lysosomal escape ability, and high AR release efficiency in vitro. In both in vitro and in vivo NAFLD models, GA-MSe@AR demonstrated more pronounced lipid-lowering and antioxidant properties than AR and GA-MSe. Additionally, GA-MSe@AR effectively targeted the liver, resulting in a greater decrease in blood glucose, lipids, ALT, AST levels, and reduction liver inflammation, as well as improved pancreatic function in high-fat diet (HFD)-fed mice compared to AR alone. Conclusion: The GA-specific modification enhanced liver-targeted accumulation of the selenium-based nanoparticles, enabling precise targeted delivery of AR. GA-MSe@AR demonstrated superior lipid-lowering efficacy and antioxidant activity in a NAFLD mice model. These findings collectively establish GA-MSe@AR as a promising therapeutic candidate for NAFLD treatment.