Cancer nanomedicine vehicles are required to cross the vascular barrier to reach the tumor site in order to ensure the successful delivery of their therapeutic load. Here, nanodiamond (ND) variants were shown to induce surface dependent vascular barrier leakiness. The ND-induced leakiness was found to be mediated by the increase in intracellular reactive oxygen species (ROS) and Ca2+. These then in turn triggered the loss in endothelial ceD-endothelial cell connections of the vascular barrier and also triggered their quasi-stable cytoskeletal remodelling. This ND driven increase in leakiness allowed more doxorubicin drug to penetrate through the vascular barrier to reach the cancer cells. This increase in the doxorubicin penetration subsequently led to an increase In the cancer killing effect. Overall, tuning the vascular barrier leakiness through ND surface group functionalization could provide an alternative strategy for the cancer nanomedicine to traverse across the vascular barrier.