Nanoparticles (NPs) are engineered particles in the nanometer range used as carriers to deliver drugs to the target sites and avoid off-target drug accumulation, a concept applied for several decades in tumor targeting. Most NPs developed for cancer therapy are intravenously administered where the endothelial barrier lining the lumen of the blood vessels is the first barrier they interact with before extravasating into the target tissues. Little is known about the interaction of NPs with the endothelial barrier under conditions simulating angiogenic blood vessels of the tumor microenvironment, namely the shear stress on the endothelial cells (ECs) due to blood flow and the chromosomal abnormalities of this special population of ECs. We hypothesize that the interaction and the impact of NPs on the ECs are influenced by the shear stress and the chromosomal instability or aneuploidy of ECs. As conventional models are static, they fail to account for the dynamism seen physiologically, resulting in discrepancies between in vitro and in vivo experiments. Therefore, we will rely on microfluidic cell models (organ-on-a-chip models) that expose the cells cultured in microscale channels to fluids at highly controlled and replicable flow conditions mimicking in vivo scenarios while using minimum resources. We have used vessel-on-a-chip models to evaluate a novel class of indium-based quantum dots (QDs) and compared the results to conventional cadmium-based QDs. Overall, our results support our hypothesis that dynamic conditions and cell aneuploidy result in different cell phenotypes resulting in different cell responses, mainly cell viability and cell uptake of QDs. Results in this study are believed to direct future research lines towards minimizing the discrepancies between in vitro and in vivo responses and better defining cell responses of NPs using physiologically relevant in vitro cell-based assays.