Redox-Unlockable Nanoparticle-Based MST1 Delivery System to Attenuate Hepatic Steatosis via the AMPK/SREBP-1c Signaling Axis

Abstract

To date, few effective treatments have been licensed for nonalcoholic fatty liver disease (NAFLD), which a kind of chronic liver disease. Mammalian sterile 20-like kinase 1 (MST1) is reported to be involved in the development of NAFLD. Thus, we evaluated the suitability of a redox-unlockable polymeric nanoparticle Hep@PGEA vector to deliver MST1 or siMST1 (HCP/MST1 or HCP/siMST1) for NAFLD therapy. The Hep@PGEA vector can efficiently deliver the condensed functional nucleic acids MST1 or siMST1 into NAFLD-affected mouse liver to upregulate or downregulate MST1 expression. The HCP/MST1 complexes significantly improved liver insulin resistance sensitivity and reduced liver damage and lipid accumulation by the AMPK/SREBP-1c pathway without significant adverse events. Instead, HCP/siMST1 delivery exacerbates the NAFLD. The analysis of NAFLD patient samples further clarified the role of MST1 in the development of hepatic steatosis in patients with NAFLD. The MST1-based gene intervention is of considerable potential for clinical NAFLD therapy, and the Hep@PGEA vector provides a promising option for NAFLD gene therapy.