Inhalation metal-phenolic nanozyme as a novel therapeutic strategy for lung ischemia-reperfusion injury

Background Lung ischemia-reperfusion injury (LIRI) is a complex pathophysiological process with few existing therapeutic options. New drugs are needed to target both oxidative stress and enhanced sterile inflammation during ischemia-reperfusion. Results In this study, we developed a metal-phenolic nanozyme (CurFe) that possesses significant enzyme-like activities, including superoxide dismutase (SOD)-like activity and hydroxyl radical (•OH) scavenging ability, and can effectively modulate inflammatory cytokines and maintain cellular homeostasis in vitro. In the mouse LIRI model, nebulized inhalation of Cur-Fe nanozyme significantly reduced lung inflammation and oxidative stress, improved lung tissue function, and restored alveolar structure. It is important to note that transcriptomics and metabolomics analyses demonstrated that Cur-Fe nanozyme modulated key metabolic pathways, including the cGMP-PKG signaling pathway and amino acid metabolism, thereby promoting its protective effects on lung tissue. Conclusion In this study, we present a Cur-Fe nanozyme that shows great potential in mitigating LIRI-associated lung injury by targeting oxidative stress and inflammation as well as regulating key transcriptional and metabolic pathways. This innovative approach provides a new avenue for the development of nanomedicines for the treatment of ischemia-reperfusion-related diseases with promising clinical applications.