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Treatment of the ischemic stroke has remained a major healthcare challenge. The phenolic compound, ferulic acid (FA), has shown promising antioxidant and neuroprotective effects, however, low bioavailability may negatively affect its efficiency. This, prompted us to incorporate FA into the nanostructured lipid carriers (FA-NLCs) and evaluate its therapeutic potential in in vitro and in vivo models of ischemic stroke.FA-NLCs were prepared by high-pressure homogenization followed by physicochemical characterization, evaluation of the bioactivity of FA-NLCs in oxygen-glucose deprivation (OGD) and global cerebral ischemia/reperfusion (I/R) injury and implication of phosphatidylinositol 3-kinase (PI3K) pathway in this regard.Formation of FA-NLCs which exhibited a controlled release profile, was confirmed by scanning electron microscope and differential scanning calorimetry. 1- and 8-h OGD followed by 24 h re-oxygenation significantly reduced PC12 cell viability, increased lactate dehydrogenase activity and number of condensed nuclei, and induced oxidative stress as revealed by increased malondialdehyde and decreased glutathione content and superoxide dismutase and catalase activities. FA (80 and 100 μM) reduced the cytotoxicity, oxidative stress, and cellular damage only after 1-h OGD, while, FA-NLCs (containing 80 and 100 μM of FA) were effective at both time points. Intravenous injections of FA-NLCs (20 and 25 mg/kg) into rats significantly attenuated I/R-induced neurobehavioural deficits, cellular damage, and oxidative stress, while, FA failed. Pre-treatment with PI3K inhibitor, LY294002, abolished the protective effects against OGD or I/R.FA-NLCs by improving the pharmacological profile of FA and activating PI3K pathway might be of therapeutic value in cerebral stroke.