There is a dearth in fundamental cellular-level understanding of how nanoparticles interact with the cells of the blood brain barrier (BBB), particularly under the oxidative environment. The apoptosis of cerebral microvessel enclothelial cells (CMECs) induced by oxidative stress injury plays a key role in the dysfunction of BBB. By use of CMECs as an in vitro BBB model, we show for the first time that C(60)(C(COOH)(2))(2) nanoparticles can selectively enter oxidized CMECs rather than normal cells, and maintain CMECs integrity by attenuating H(2)O(2)-induced F-actin depolymerization via the observation of several state-of-the art microscopic techniques. Additionally, we have found that C(60)(C(COOH)(2))(2) nanoparticles greatly inhibit the apoptosis of CMECs induced by H(2)O(2), which is related to their modulation of the JNK pathway. C(60)(C(COOH)(2))(2) nanoparticles can regulate several downstream signaling events related to the JNK pathway, including reduction of JNK phosphorylation, activation of activator protein 1 (AP-1) and caspase-3, and inhibition of polyADP-ribose polymerase (PARP) cleavage and mitochondrial cytochrome c release. Our results indicate that C(60)(C(COOH)(2))(2) nanoparticles possess a novel ability of selectively entering oxidation-damaged cerebral enclothelial cells rather than normal enclothelial cells and then protecting them from apoptosis.