Amorphous Ce–Mn–O Bimetallic Oxide Nanoparticles Simultaneously Activate SOD1 and SOD2 for Enhanced Therapy of Acute Respiratory Distress Syndrome

Oxidative stress caused by the excessive accumulation of reactive oxygen species (ROS) plays a critical role in the development of acute respiratory distress syndrome (ARDS). Current antioxidant therapies using organic ROS scavengers fail in decreasing mortality due to the low ROS scavenging activity and fast metabolic rate. Inorganic ROS scavenging nanoparticles provide potential options for investigating ARDS antioxidant therapy. However, previous studies mainly focus on the ROS scavenging activity of these nanoparticles, while their capability to modulate the endogenous antioxidant system remains largely unexplored. Herein, mesoporous Ce-Mn-O bimetallic oxide nanoparticles (NPCeMn) are designed and synthesized to activate the endogenous antioxidant system for ARDS therapy. Morphologically similar ceria nanoparticles (NPCe) and manganese oxide nanoparticles (NPMn) are used for comparison. In vivo and in vitro results demonstrate that NPCe and NPMn can promote the expression of SOD1 and SOD2, respectively, while NPCeMn can promote the expression of both SOD1 and SOD2. Mechanism studies establish a Keap1/Nrf2/SOD axis through which NPCeMn acts to activate the endogenous antioxidant system. Based on this property, NPCeMn can effectively alleviate oxidative stress and inflammation in the lung of the murine ARDS model. These findings suggest that activating the endogenous antioxidant system via inorganic nanoparticles is a promising ARDS therapeutic strategy.