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Endothelial leakiness or permeability directly determines the access of any bionanotechnology to the target tissue site. Currently, cancer nanotechnology relies on tumor-derived endothelial leakiness, which suffers from unreliability, inhomogeneity of leakiness, and uncontrollability. Nanomaterials by themselves are capable of inducing endothelial leakiness (NanoEL) without any tumor involvement by targeting the endothelial cell junctions; this NanoEL phenomenon not well understood. Here, we showed that the negatively charged Au nanoparticles (NPs) induce significantly higher NanoEL than positively charged nanoparticles. We hypothesized and showed that in both in vitro and in silico models that cell junction targeting arose for the negatively charged particles due to a succession of repulsive-sedimentary interactions between the negative particle and the negatively charged glycocalyx found on the cell membrane surface. On the contrary, NPs with positive charges are attracted stably by the negatively charged glycocalyx and remained in situ for long enough, which eventually are endocytosized into the cells as contrasted to localization toward the cell junction. There are implications to how nanoparticle charges could be tuned to induce (or avoid) endothelial leakiness by design. [ABSTRACT FROM AUTHOR]