Effective intervention against ischemic stroke requires delivery of potent neuroprotective drugs to the brain. Tanshinone IIA (TSIIA), the major bioactive ingredient extracted from the root of Salvia miltiorrhiza Bunge, is a proven neuroprotective compound, but its therapeutic application is hampered by chemical instability, low solubility, and inability to cross the blood brain barrier (BBB). Herein we report that a nanoformulation with a high-loading of TSIIA functionalized with Angiopep-2 effectively increased its brain accumulation by ∼12 fold, reduced infarct volume in an experimental stroke model by 2 fold, and augmented rat motor function scores after stroke by 60%. We confirm that the anti-ischemic stroke is mediated by inhibition of neuronal apoptosis, depletion of proinflammatory cytokines, and reversal of intracellular calcium [Ca2+]i overload in neurons. Moreover, we reveal for the first time that the underlying molecular mechanism for this formulation of TSIIA involves inhibition of the inflammatory signaling pathway HMGB1/TLRs/MyD88/NF-κB.
