Nanoparticle technology is undergoing significant expansion largely because of the potential of nanoparticles as biomaterials, drug delivery vehicles, cancer therapeutics, and immunopotentiators. Incorporation of nanoparticle technologies for in vivo applications increases the urgency to characterize nanomaterial immunogenicity. This study explores titanium dioxide, one of the most widely manufactured nanomaterials, synthesized into its three most common nanoarchitectures: anatase (7-10 nm), rutile (15-20 nm), and nanotube (10-15 nm diameters, 70-150 nm length). The fully human autologous MIMIC immunological construct has been utilized as a predictive, nonanimal alternative to diagnose nanoparticle immunogenicity. Cumulatively, treatment with titanium dioxide nanoparticles in the MIMIC system led to elevated levels of proinflammatory cytokines and increased maturation and expression of costimulatory molecules on dendritic cells. Additionally, these treatments effectively primed activation and proliferation of naive CD4(+) T cells in comparison to dendritic cells treated with micrometer-sized (>1 microm) titanium dioxide, characteristic of an in vivo inflammatory response.