||Phagocytes are important players in host exposure to nanomaterials, by processing nanomaterials and possibly contributing to host nanotoxicity. Macrophages in particular are believed to be among the "first responders" and primary cell types that uptake and process nanoparticles, mediating host biological responses by subsequent interactions with inflammatory signal pathways and immune cells. Thus, it is important to understand how nanomaterials are recognized, internalized, trafficked and distributed within this cell type and how this cell-based reaction furthers responses in vivo. This dissertation will focus on describing macrophage-based silica nanoparticle exposure, mechanisms of uptake, intracellular fate and potential initiation of downstream immunological processes, as a function of physicochemical properties such as size, surface properties and geometry. Alterations in physicochemical properties, specifically geometry of nanomaterials, can influence cellular uptake mechanisms. Specific macrophage phenotypes are shown to induce nanoparticle uptake in vitro and in vivo. Mechanistic evaluation has provided evidence of cellular machinery inducing autonomous antimicrobial defense and cytoplasmic clearance mechanisms such as autophagy in response to positively charged silica nanoparticle exposure. Understanding nanoparticle macrophage interactions may allow for the development of platforms to design biocompatible systems for specific intracellular uptake and fate.