Betulinic acid NPs were employed as a bioactive multifunctional vehicle to markedly increase the delivery of glyburide to the brain, leading to synergetic effects for ischemic stroke by nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO-1) antioxidant pathway, compared with either glyburide or betulinic acid NPs. This evidence concerns the gene NFE2L2 and ischemic stroke.