Sulfur‐Fumigation Engineered Ceria Nanoparticles With Augmented Oxygen Vacancies for Enhanced Therapy of Drug‐Induced Liver Injury

The excessive generation of reactive oxygen species (ROS) and its synergistic interplay with inflammation and apoptosis play a critical role in the progression of drug-induced liver injury (DILI). Ceria nanoparticles are potential DILI therapy candidates due to their self-renewable ROS scavenging activity. However, the clinical translation of ceria nanoparticles for DILI therapy is challenged by enhanced ROS scavenging activity and prolonged hepatic retention. Herein, the sulfur-fumigation approach is used to modulate the ROS scavenging activity of ceria nanoparticles through the surface microstructure reconfiguration mechanism. The sulfur-fumigation induces nanoparticle contraction and crystalline fusion. Crucially, sulfur-fumigation decreases (111) plane exposure but increases (200) and (220) plane exposure. These changes cause the generation of abundant oxygen vacancies, which significantly enhances the ROS scavenging activity of ceria nanoparticles, even when the surface area is decreased. Together with an appropriate hydrodynamic diameter (135.9 nm) for liver targeting, the sulfur-fumigated ceria nanoparticles can easily accumulate in the liver and alleviate ROS, inflammation, and apoptosis in DILI mice. Compared to the clinical standard N-acetylcysteine (NAC), the sulfur-fumigated ceria nanoparticles show better therapeutic efficacy across most of the detected parameters. These findings suggest that sulfur-fumigation is a potent surface reconfiguration strategy to engineer highly active ceria nanoparticles for DILI therapy.