Previous reports have shown that nanoparticles (NPs) can both enhance and suppress immune effector functions; however the mechanisms that dictate these responses are still unclear. Here, the effects of polyacrylic acid (PAA) functionalized metal-oxide NP are investigated on RBL-2H3 (representative mammalian granulocyte-like cell line) cell viability, cellular degranulation, immunoglobulin E (IgE) receptor binding, and cell signaling pathways related to immune function. The increasing development of PAA-NPs as pesticide dispersants and as drug carriers in therapeutics necessitates their investigation for safe production. Using two in vitro experimental approaches, this study demonstrates that pre-exposing RBL-2H3 cells, or IgE antibodies, to PAA-NPs (TiO2, CeO2, ZnO, Fe2O3, and PAA-Capsules (NP coating control) over 24 h, significantly decrease the binding capacity of IgE for Fcε receptors, inhibit the phosphorylation of intracellular signaling proteins (e.g., MAPK ERK) that mediate degranulation, and inhibited RBL-2H3 cell degranulation. In addition, and unlike the other NPs tested, PAA-TiO2 significantly reduced RBL-2H3 viability, in a time (4-24 h) and dose-dependent manner (>50 μg mL-1). Together, these data demonstrate that PAA-NPs at sub-lethal doses can interact with cell surface structures, such as receptors, to suppress various stages of the RBL-2H3 degranulatory response to external stimuli, and modify immune cell functions that can impact host-immunity.