With the increased prevalence of
nonalcoholic steatohepatitis (NASH) in the world, effective
pharmacotherapy in clinical practice is still lacking. Previous studies have shown that
dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a
reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of
bilirubin to poly(
ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of
nonalcoholic steatohepatitis (NASH). The PEGylated
bilirubin can self-assemble into nanoparticles in an aqueous
solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved
glucose intolerance, relieved hepatic
lipid accumulation and
inflammation, and ameliorated NASH-induced
liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.