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

Abstract 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 (CeO 2 ‐rHDL) is engineered to overcome the aggregation tendency and targeting limitation of naked ceria nanoparticles. These findings revealed that CeO 2 ‐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, CeO 2 ‐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.