Lipoprotein-Based Nanocatalyst Enables Targeted Treatment of APAP-Induced Liver Injury via Enhanced Macropinocytosis

Drug-induced liver injury (DILI), predominantly caused by acetaminophen (APAP) overdose, is characterized by excessive Reactive Oxygen Species (ROS) production and subsequent hepatocyte necrosis. Although N-acetylcysteine (NAC) remains the only approved treatment, its effectiveness is limited by a narrow therapeutic time window and reduced efficacy in advanced cases. To address these limitations, an innovative therapeutic approach is developed utilizing ceria's antioxidant properties. In this study, a reconstituted high-density lipoprotein-encapsulated ceria nanocatalyst (CeO₂-rHDL) is engineered to overcome the aggregation tendency and targeting limitation of naked ceria nanoparticles. These findings revealed that CeO₂-rHDL enters hepatocytes through macropinocytosis, a process synergistically enhanced by both APAP and NAC, facilitating efficient liver targeting. The nanocatalyst demonstrated remarkable therapeutic efficacy by restoring mitochondrial function through ROS reduction. When combined with NAC, CeO₂-rHDL significantly improved survival outcomes in DILI mice. This lipoprotein-based nanocatalyst system represents a promising therapeutic strategy for DILI treatment, offering enhanced targeting capabilities and improved therapeutic efficacy.

N‐acetylcysteine; acetaminophen‐induced liver injury; cerium oxide; lipoprotein nanostructure; macropinocytosis; nanocatalyst.