Elevated levels of reactive oxygen species (ROS) are implicated in the onset and progression of many diseases, e.g., virus infection, ischemic stroke and neurodegenerative diseases. ROS-scavenging nanomaterials have attracted particular interest. Here, we report the development of a natural protein nanocage named Dps for in vitro and in vivo antioxidant treatment by inhibiting the Fenton reaction, a critical step in ROS generation and interconversion. Systematic surface engineering enabled cell penetration, good colloidal stability, and facile purification of Dps. With its intrinsic ferroxidase activity consuming both H2O2 and Fe2+, Dps not only protects human cells from oxidative stress but also effectively alleviates ROS-induced inflammation in a mouse dermatitis model. The protection is triggered by elevated H2O2 and thereby, in principle, avoids ROS imbalances. Thus, Dps has potential as a new bionano platform for different purposes, such as antiaging, anti-inflammation and cosmetics.