An effective antioxidant to mitigate reperfusion injury by tailoring CeO2 electronic structure on layered double hydroxide nanosheets

Highly effective antioxidants are needed to attenuate ischemia/reperfusion-induced reactive oxygen species (ROS) and inflammation as a way to alleviate the secondary injury of brain tissue from reperfusion. Herein, we propose the utilization of a two-dimensional (2D) layered double hydroxide (LDH) to optimize the activity of integrated CeO2, hence modifying the electron structure and density of Ce active sites. Through modulation of the surface-to-volume ratio of Ce active sites and Ce3+/(Ce3+ + Ce4+) of the integrated CeO2, the composite-type CeO2@LDH (C-CL) reduces the reaction barrier in the rate-limiting step (from *H2O2 to *O2) for H2O2 decomposition. As a result, in vitro experiments demonstrate that C-CL exhibits 1.6 times higher superoxide dismutase (SOD)-like activity than CeO2, with a remarkable •OH scavenging rate of 86.8%. Moreover, C-CL effectively simulates catalase (CAT)-like activity with Michaelis-Menten constant (Km) value of 18.63 mM, which facilitates H2O2 decomposition. Meanwhile, in vivo experiments reveal that C-CL treatment significantly reduces the infarct area from 36.4% to 4.1% after reperfusion therapy, accompanied by a decrease in neurological deficit score from 4.4 to 0.6. In conclusion, C-CL exhibits immense potential for mitigating reperfusion injury in ischemic stroke. Therefore, this strategy provides a new insight for designing high-performance antioxidants to treat ROS-related diseases, by modulating the density of active sites and altering the electronic state of antioxidants based on 2D materials.