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Oxidative stress is associated with many acute and chronic inflammatory diseases. Development of nanomaterial-based enzyme mimetics for reactive oxygen species (ROS) scavenging is challenging, but holds great promise for the treatment of inflammatory diseases. Herein, we report the highly ordered manganese dioxide encapsulated selenium-melanin (Se@Me@MnO2) nanozyme with high efficiency for intracellular antioxidation and anti-inflammation. The Se@Me@MnO2 nanozyme is sequentially fabricated through the radical polymerization and the in-situ oxidation-reduction. In vitro experimental results demonstrated that the Se@Me@MnO2 nanozyme exhibits multiple enzyme activities to scavenge ROS, including catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). Mechanism researches illustrated that the Se core possesses GPx-like catalytic activity, the Me and the MnO2 possess both the SOD-like and the CAT-like activities. What’s more, due to the stable unpaired electrons existing in the nanozyme, the Se, Me and MnO2 provide synergistic and fast electron transfer effect to achieve the quickly scavenging of hydrogen peroxide, hydroxyl radical, and superoxide anion. Further in vivo experimental results showed that this biocompatible nanozyme exhibits cytoprotective effects by resisting ROS-mediated damage, thereby alleviating the inflammation. This multienzyme mimetics is believed to be an excellent ROS scavenger and have a good potential in clinical therapy for ROS-related diseases.