Metabolic dysfunction-associated steatohepatitis treated by poly(ethylene glycol)-block-poly(cysteine) block...

Non-alcoholic steatohepatitis (NASH), now known as metabolic dysfunction-associated steatohepatitis (MASH), involves oxidative stress caused by the overproduction of reactive oxygen species (ROS). Small-molecule antioxidants have not been approved for antioxidant chemotherapy because of severe adverse effects that collapse redox homeostasis, even in healthy tissues. To overcome these disadvantages, we have been developing poly(ethylene glycol)-block-poly(cysteine) (PEG-block-PCys)-based self-assembling polymer nanoparticles (Nano^Cyses), releasing Cys after in vivo degradation by endogenous enzymes, to obtain antioxidant effects without adverse effects. However, a comprehensive investigation of the effects of polymer design on therapeutic outcomes has not yet been conducted to develop our Nano^Cys system for antioxidant chemotherapy. In this study, we synthesized different poly(_L-cysteine) (PCys) chains whose sulfanyl groups were protected by tert-butyl thiol (StBu) and butyryl (Bu) groups to change the reactivity of the side chains, affording Nano^Cys(SS) and Nano^Cys(Bu), respectively. To elucidate the importance of the polymer design, these Nano^Cyses were orally administered to MASH model mice as a model of oxidative stress-related diseases. Consequently, the acyl-protective Nano^Cys(Bu) significantly suppressed hepatic lipid accumulation and oxidative stress compared to Nano^Cys(SS). Furthermore, we substantiated that shorter PCys were much better than longer PCys for therapeutic outcomes and the effects related to the liberation properties of Cys from these nanoparticles. Owing to its antioxidant functions, Nano^Cyses also significantly attenuated hepatic inflammation and fibrosis in the MASH mouse model.