Excessive production of reactive oxygen species (ROS) after cerebral ischemia and reperfusion is implicated in brain damage through different cellular and molecular mechanisms, and it is further aggravated by impaired cellular antioxidant defense systems under ischemic conditions. Therapeutic strategies based on exogenous delivery of the native form of superoxide dismutase (SOD), a free radical scavenger, are limited because of its short half-life (6 min) in vivo and poor permeability across the blood-brain-barrier (BBB). We encapsulated SOD in biodegradable poly(D,L-lactide co-glycolide) nanoparticles (SOD-NPs) and tested their efficacy in a rat focal cerebral ischemia-reperfusion injury model. We hypothesized that localized brain delivery of SOD-NPs would sustain the protective effect of SOD by neutralizing the deleterious effects of ROS formed following ischemia-reperfusion. SOD-NPs were administered at the time of reperfusion via the intracarotid route to maximize their localization in the brain. Animals receiving SOD-NPs (10,000 U of SOD/kg) demonstrated a 65% reduction in infarct volume, whereas an equivalent dose of SOD in solution (SOD-Sol) increased it by 25% over saline control (P<0.001; data at 6 h following reperfusion). Control NPs alone or mixed with SOD-Sol were ineffective in reducing infract volume, with results similar to saline control, indicating the protective effect of the encapsulated enzyme. SOD-NPs maintained BBB integrity, thereby preventing edema, reduced the level of ROS formed following reperfusion, and protected neurons from undergoing apoptosis. Animals treated with SOD-NPs demonstrated greater survival than those with saline control (75% vs. 0% at 28 days) and later regained most vital neurological functions. SOD-NPs may be an effective treatment option in conjunction with a thrombolytic agent for stroke patients.—Reddy, M. K., Labhasetwar, V. Nanoparticle-mediated delivery of superoxide dismutase to the brain: an effective strategy to reduce ischemia-reperfusion injury.