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Intracerebral hemorrhage (ICH) is a devastating form of stroke with high mortality and morbidity. It is more severe than ischemic stroke and half of the patients die during the first month following the attack. The pathogenesis of ICH injury is complex and it involves primary insult triggered by hematoma mass effect and secondary insult triggered by brain tissue response to hematoma constituents. Cofilin, a ubiquitous actin associated protein, was found to be involved in many neurodegenerative diseases. Disruption of cofilin dynamics leads to cofilin-actin rod formation in different cellular compartments initiating neuronal cell death and apoptosis. In the present study, nanoparticle delivery of small interfering RNA (siRNA) to silence cofilin and investigate its effects using in vitro and in vivo models of inflammation. In primary cortical neurons subjected to oxygen and glucose deprivation, an ischemia model, cofilin was found to be highly activated and resulted in neuronal apoptosis, which was significantly inhibited by cofilin knockdown using siRNA. In microglia, cofilin knockdown significantly inhibited LPS-induced microglial cell activation through antagonizing NF-κB and JAK-STAT pathways. The release of proinflammatory mediators, microglial proliferation and microglial migration rates were significantly reduced by cofilin knockdown. In collagenase-induced ICH in mice, cofilin expression and phosphorylation was found to be significantly upregulated in the perihematomal area. Importantly, cofilin knockdown by using cofilin siRNA significantly reduced the volume of injury and improved the neurobehavioral deficits via combating oxidative/nitrosative stress and modulating neuroinflammation. In conclusion, targeting cofilin activity in diseases involving inflammation could become a novel therapeutic drug intervention.