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The multidisciplinary field of nanotechnology has allowed for unprecedented exploration and manipulation of molecular, sub-molecular, and atomic structures and advancements in this field are revolutionizing scientific thought and applications. Within the field of nanotechnology, the branch of nanobiotechnology focuses on studying the effects of nanomaterials on biological systems and to elucidate how nanomaterials interact with cells and cellular components. Nanoparticles are a particular type of nanomaterial whose dimensions measure 100 nanometers and are shown to possess unique size-dependent physical, chemical and biological properties compared to their bulk counterparts. Metal oxide nanoparticles, such as those made from ZnO, are a type of nanomaterial found in many different industrial products such as sunscreen, food preservatives and clothing. Due to the prevalence of ZnO nanoparticles in the environment, there is an urgent need to gain an understanding of how these particles interact with biological systems, and due to the fact that nanoparticles are within the range of many different naturally occurring biological molecules, research investigating nanoparticle-cell interactions may offer innovative approaches for the development of novel biomedical applications. This research focuses on examining the effects of metal oxide based nanoparticles, including ZnO, on immune cells and investigates cell-specific responses and mechanisms of toxicity. Collectively, our results demonstrate differential ZnO NP toxicity based on cell-type, activation status, and NP size with highly proliferative/rapidly diving cells (e.g. cancer cells and activated T cells) killed at lower concentrations of ZnO nanoparticles compared to normal cells. In addition, an inverse relationship between nanoparticle size and cytotoxicity was observed. Further, these results implicate ROS production as a major mechanism of ZnO-NP induced cytotoxicity capable of inducing apoptosis in human immune cells, and reveal ZnO NP induce pro-inflammatory cytokine production (e.g. IFN-y, TNF-α and IL-12). Exploitation of the preferential nanoparticle-mediated toxicity observed in these studies may provide a foundation for the design and development of novel ZnO nanoparticle based biomedical applications and therapeutics for the treatment of human diseases, such as cancer and autoimmune disorders.