Exosome‐Functionalized Self‐Carrier Enzyme‐Like/Drug With Triple Amplified Anti‐Oxidative Stress for Synergistic Depression Therapy

Abstract Depression, a severe disorder affecting both physical and mental health, is commonly treated with first‐line antidepressants, which often exhibit limited efficacy due to poor penetration of the blood‐brain barrier (BBB) and significant side effects, thus requiring the exploitation of biocompatible and effective treatments. Recent studies suggest that depression is closely linked to an imbalance in oxidative stress and subsequent inflammatory responses. Antioxidant therapies and targeting oxidative stress in inflammatory depression are therefore emerging as promising strategies. In this study, an exosome‐functionalized and geniposide (GEN) self‐carried Prussian blue (PB) nanotherapeutic approach is fabricated to realize efficient BBB penetration for synergistic depression therapy. The porous PB carrier possesses multi‐enzyme capabilities, which can effectively scavenge the accumulated ROS, protecting the slightly inflammatory acidic environment released GEN from oxidation, and the GEN subsequently works simultaneously with PB to activate the Nrf2‐ARE pathway, enhancing the body's oxidative stress defense mechanisms synergistically. The triple‐amplified anti‐oxidant strategy of this nanomaterial is shown to mitigate microglial activation and the reduction in neuroplasticity, ultimately alleviating the pathological markers of inflammatory depression. Overall, the constructed nanomaterials underscore the therapeutic potential of anti‐oxidative stress for synergistic removal of ROS and activation of the Nrf2‐ARE pathway in the treatment of inflammatory depression.