A Biomimetic Nanoparticle Exerting Protection against Acute Liver Failure by Suppressing CYP2E1 Activity and Scavenging Excessive ROS

Acute liver failure (ALF) is a severe liver disease caused by many reasons. One of them is the overdosed acetaminophen (APAP), which is metabolized into N‐acetyl‐p‐benzoquinone imine (NAPQI), an excessive toxic metabolite, by CYP2E1, resulting in excessive reactive oxygen species (ROS), exhausted glutathione (GSH), and thereafter hepatocyte necrosis. N‐acetylcysteine is the Food and Drug Administration‐approved drug for detoxification of APAP, but it has limited clinical application due to the short therapeutic time window and concentration‐related adverse effects. In this study, a carrier‐free and bilirubin dotted nanoparticle (B/BG@N) is developed, which is formed using bilirubin and 18β‐Glycyrrhetinic acid, and bovine serum albumin (BSA) is then adsorbed to mimic the in vivo behavior of the conjugated bilirubin for hitchhiking. The results demonstrate that B/BG@N can effectively reduce the production of NAPQI as well as exhibit antioxidant effects against intracellular oxidative stress via regulating the nuclear factor erythroid 2‐related factor 2/heme oxygenase‐1 signal axis and reducing the production of inflammatory factors. In vivo study shows that B/BG@N can effectively improve the clinical symptom of the mice model. This study suggests that B/BG@N own increases circulation half‐life, improves accumulation in the liver, and dual detoxification, providing a promising strategy for clinical ALF treatment. Carrier‐free, bilirubin‐dotted, and albumin‐bound 18β‐glycyrrhetinic acid nanoparticles (B/BG@N) are developed to mimic the in vivo behavior of the conjugated bilirubin in the body for liver‐targeted delivery as well as exert dual detoxification by scavenging reactive oxygen species and inhibiting CYP2E1 for acute liver failure therapy.