ROS‐Response Nanoparticles for Edaravone Delivery: Pathological‐Activated Neuroprotection Against Ischemic‐Reperfusion Injury in Ischemic Stroke

Ischemic stroke is a leading cause of mortality and disability, with ischemia-reperfusion injury exacerbating neuronal damage and neuroinflammation due to pathologically activated reactive oxygen species (ROS) production in the ischemic penumbra. Edaravone, a free radical scavenger, is approved for the clinical treatment of ischemic stroke. However, edaravone directly decreases ROS even at low concentrations, which may inhibit the physiological effects of ROS and largely limit the clinical application of edaravone. To overcome this challenge, a ROS-response nanoparticle system, edaravone-loaded DEX-CDIPBE (DEX-CDIPBE-ED), is developed for the selectively releasing edaravone in the ischemic penumbra during reperfusion, mitigating oxidative stress while minimizing off-target effects. DEX-CDIPBE-ED produces potent antioxidant and neuroprotective effects in neuronal cells mimicking ischemic and/or reperfusion phases of ischemic stroke. DEX-CDIPBE-ED further prevents behavioral deficits, reduces oxidative stress, and inhibites neuroinflammation with a higher potency than edaravone in the ischemic penumbra in middle cerebral artery occlusion/reperfusion (MCAO/R)-treated rats. These findings highlight the potential of DEX-CDIPBE-ED as a pathological activated antioxidative therapy for ischemic stroke, offering enhanced neuroprotection and reduced systemic toxicity.