Rapidly Liver-Accumulating BiOCl@ITA Nanozyme for Synergistic ROS Scavenging and Macrophage Reprogramming in APAP-Induced Liver Injury.

Abstract

Acetaminophen (APAP) overdose is the leading cause of acute liver failure worldwide, yet existing therapy relies solely on N-acetylcysteine (NAC), whose efficacy diminishes markedly beyond an 8-10 h therapeutic window. The underlying pathology involves a self-amplifying cycle of reactive oxygen species (ROS) overproduction and macrophage-mediated inflammation, and strategies that concurrently scavenge ROS, reprogram macrophage polarization, and attenuate hepatocyte apoptosis remain lacking. Itaconate (ITA), an endogenous anti-inflammatory metabolite, suffers from poor membrane permeability and lacks intrinsic ROS-scavenging capacity. Herein, we constructed BiOCl@ITA by integrating defect-engineered bismuth oxychloride (BiOCl) with surface-loaded ITA. Oxygen vacancy engineering confers intrinsic superoxide dismutase (SOD)- and catalase (CAT)-mimicking activities under stimulus-free conditions. BiOCl@ITA showed rapid accumulation in the liver within 0.5 h after intraperitoneal administration and was efficiently internalized by both hepatocytes and macrophages in vitro. Moreover, BiOCl@ITA virtually eliminated intracellular ROS and attenuated APAP-induced hepatocyte injury, while also reprogramming LPS-stimulated macrophages from M1 toward an M2 phenotype, consistently outperforming free ITA across all endpoints. In a murine APAP-induced ALI model, BiOCl@ITA-treated mice showed near-complete thermal recovery by 24 h, accompanied by substantially reduced serum hepatic injury markers and attenuated histopathological damage. Hepatic molecular and tissue-level analyses further demonstrated restoration of antioxidant defenses, favorable regulation of BAX/BCL-2 expression, and sustained M1-to-M2 macrophage polarization in vivo. These findings demonstrate that BiOCl@ITA synergistically integrates catalytic ROS detoxification with ITA-mediated macrophage reprogramming, offering a promising therapeutic approach for APAP-induced acute liver injury.