High-Density Lipoprotein Nanoparticles Loaded with Silybin for Therapy of Drug-Induced Liver Injury

Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF), driven biological processes such as oxidative damage and mitochondrial dysfunction High-density lipoproteins (HDL), a natural nanoparticle that could deliver HDL cholesteryl ester into hepatocytes via class B type I scavenger receptors (SR-BI), have shown the potential as drug delivery systems for therapeutic applications. In this study, silybin (SIL) was encapsulated in biomimetic synthetic nanoparticles (SIL-HDL), and its therapeutic efficacy against DILI was evaluated. SIL-HDL exhibited a small and uniform particle size, stable physicochemical properties, and enhanced cellular uptake in vitro, as well as improved liver targeting in vivo. Additionally, SIL-HDL enhanced the antioxidant and anti-inflammatory effects of SIL. SIL-HDL improved liver function and inhibited liver necrosis, demonstrating protective effects against DILI. Western blot analysis indicated that the SIL-HDL significantly influenced AMPK/JNK and Nrf2/KEAP1 signaling pathways. These findings suggest that SIL-HDL enhances the therapeutic efficacy of SIL, and it is a promising candidate for treating acetaminophen (APAP)-induced DILI.