Nanotechnology is an emerging branch of applied science and technology for designing tools and devices of size 1-100 nm. Engineered nanomaterials (ENMs) have been widely used in several fields from medical to electronics and possess unique chemical, biological and physical properties (e.g., thermal and optical properties, solubility, fluorescence, electrical parameters) as compared to their bulk material. The increasing interest for these advanced technologies has led to great excitement about potential benefits, but little is known about the potential effects of ENM exposure on environment and human health. Due to their nano-size and large surface-to-mass ratio, ENMs may interact with several biomolecules, mainly proteins, upon contact with biological fluids forming the so-called “protein corona”. Toxicity and biocompatibility of these materials may depend predominantly on the formation of protein corona, which influence also cell interactions, localization and bioactivity of ENMs. The aim of this PhD thesis is to study the interactions of cadmium sulfide quantum dots (CdS QDs) and amorphous silica nanoparticles (SiO2 NPs) with different biological systems: yeast cells (Saccharomyces cerevisiae), human cell lines (Caco-2) and human plasma. We employed a proteomics-based approach coupled with MS analysis to determine the identities of proteins that associate to form the hard corona of these NPs for understanding the properties of ENMs that govern their interactions with proteins in biological environments. We observed that proteins involved in specific cellular pathways, as protein synthesis, are more prone to bind on NPs. Electrostatic and/or hydrophobic interactions are critical in the formation of the protein corona. Most of the identified proteins contains long disordered regions that provide flexibility to protein structure, a property that promotes their adsorption. We also focused on the possible toxicological implications of the CdS QD-corona formation in yeast, studying effects at transcriptomic, proteomic and phenotypic levels. Our results demonstrated that CdS QDs cause a general transcriptional up-regulation of genes coding for yeast corona proteins; this effect could represent a cellular mechanism in response to “physical sequestration” of the corona proteins adsorbed on CdS QD surface. Yeast mutant strains deleted in genes coding for corona proteins showed a tolerant phenotype also in presence of concentrations of CdS QDs that suppress the viability of the wild-type strain. Tolerant phenotype of these mutants suggest that the formation of protein corona may mediate the cytotoxicity of CdS QDs in yeast. Finally, using an in vitro enzymatic activity assay, we observed that adsorption onto CdS QD surface results in a dose-dependent inhibition of the activity of the GAPDH, a protein strongly associated to these ENMs. These results demonstrate that the characterization of the protein corona would be a relevant approach to predict potential toxicological effects of the ENMs.