Sustainable Nanosheet Antioxidants for Sepsis Therapy via Scavenging Intracellular Reactive Oxygen and Nitrogen Species

Sepsis is an aberrant systemic inflammatory response mediated by excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Developing an efficient antioxidant therapy for sepsis via scavenging ROS and RNS remains a big challenge owing to the insufficient activity and sustainability of conventional antioxidants. Herein, biocompatible transition-metal dichalcogenide antioxidants with excellent scavenging activity and sustainability for H₂O₂, O₂^•-, OH^•, and nitric oxide are developed for effective sepsis treatment. WS₂, MoSe₂, and WSe₂ nanosheets exfoliated and functionalized with a biocompatible polymer effectively scavenge mitochondrial and intracellular ROS and RNS in inflammatory cells. Among the nanosheets, WS₂ most efficiently suppresses the excessive secretion of inflammatory cytokines along with scavenging ROS and RNS without affecting the expression levels of the anti-inflammatory cytokine and ROS-producing enzymes. The WS₂ nanosheets significantly improve the survival rate up to 90% for severely septic mice by reducing systemic inflammation. The pharmacokinetics suggests that the WS₂ nanosheets can be excreted from mice 3 days after intravenous injection. This work demonstrates the potential of therapeutic nanosheet antioxidants for effective treatment of ROS and RNS-related diseases.