The field of nanotoxicology has made tremendous progress identifying novel and potentially adverse biological effects following nanomaterial (NM) exposure. However, one facet yet to be satisfactorily explored is how a physiological environment modifies NM physicochemical properties, thus introducing novel complexities associated with solid phase material exposures. In this study, artificial alveolar, lysosomal, and interstitial fluids were used to identify environmental-specific modulations to the properties and behavior of hydrocarbon-coated (Ag-HC) and polysaccharide-coated (Ag-PS) silver NMs. As inhalation is a common route of exposure, an alveolar macrophage cell model with deposition dosages representing approximately 2.5 months and 10 years of occupational exposure (0.5 and 25 ng/mL, respectively) were employed. Following dispersion in the artificial fluids, the Ag-HC and Ag-PS NMs demonstrated significant alterations to morphology, aggregation patterns, and particle reactivity. However, the Ag-PS also demonstrated a loss of particle coating, which elicited increased cytotoxicity, phagocytosis, and inflammation not associated with the original Ag-PS. This study demonstrated that in a physiological system NMs undergo considerable modulation, introducing a scenario where the toxicity of NMs may increase over time due to internal bioconditions. These findings highlight the critical influence that the dynamic and insoluble nature of NMs have on bioeffects and the importance of characterizing this behavior.