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

Sheng Lei,1 Qiang Wu,1 Bin Zhang,1 Minqiang Lu,1 Yu Xia,1,2 Ning Li1 1Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China; 2Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of ChinaCorrespondence: Ning Li, Department of HBP Surgery, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China, Email [email protected] Yu Xia, Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China, Email [email protected] 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. Keywords: arctiin, selenium nanoparticles, lipid deposition, oxidative stress, network pharmacology