Nanophase materials have enhanced properties (thermal, mechanical, electrical, surface reactivity, etc.) not found in bulk materials. Intuitively, the enhancement of material properties could occur when the materials encounter biological specimens. Previous investigations of biological interactions with nanometer-scale materials have been very limited. With the ability to manipulate atoms and molecules, we now can create predefined nanostructures with unprecedented precision. In parallel with this development, improved understanding of the biological effects of the nanophase materials, whatever those may be, should also deserve attention. In this study, we have applied precision aerosol technology to investigate cellular response to nanoparticles. We used synthetic nanoparticles generated by an electrospray technique to produce nanoparticles in the size range of 8–13 nm with practically monodispersed aerosol particles and approximately the same number concentration. We report here on the potency of nano-metal particles with single or binary chemical components in eliciting interleukin-8 (IL-8) production from epithelial cell lines. For single-component nanoparticles, we found that nano-Cu particles were more potent in IL-8 production than nano-Ni and nano-V particles. However, the kinetics of IL-8 production by these three nanoparticles was different, the nano-Ni being the highest among the three. When sulfuric acid was introduced to form acidified nano-Ni particles, we found that the potency of such binary-component nanoparticles in eliciting IL-8 production was increased markedly, by about six times. However, the acidified binary nano-Na and -Mg nanoparticles did not exhibit the same effects as binary nano-Ni particles did. Since Ni, a transition metal, could induce free radicals on cell surfaces, while Na and Mg could not, the acidity might have enhanced the oxidative stress caused by radicals to the cells, leading to markedly higher IL-8 production. This result indicates the complexity of biological responses to nanoparticles. We believe that the exposure methodology and aerosol technology employed in our research will provide an effective means to systematically investigate cellular responses to nanoparticles, structured or unstructured, in ongoing research projects. Different cell lines, chemicals, and particle morphology can also be investigated using such a methodology.