Due to the rapid expansion of nanotechnology and the increasing applications of nanomaterials under production and development, it is essential evaluate the potential impacts on human health, ecosystems and the environment. This study is specifically focused on the interactions between metal-based nanoparticles (NPs) and target cells, aiming at exploration of the fundamental knowledge essentially useful for understanding nanotoxicity and its connections with particle properties. The whole structure of this study can be divided into three levels: the first level is to quantitatively understand physicochemical properties of NPs of interest and their dynamic changes under varying environmental conditions. The second level is to evaluate the biological interactions of representative NPs with a specific focus on the size-dependent adsorption processes, interfacial forces, cellular disruption, and membrane damages. The third level is to develop effective, accurate, and valid tools based on atomic force microscopy (AFM) to characterize NPs in terms of the nanoscale hydrophobicity and the nanoscale electric properties, which are most relevant and important properties in the bio-nano interactions. Overall, this study systematically investigated the kinetic environmental behaviors, biological interactions, and unique nano-properties of metal-based NPs, which should be of interest to people in application and implication of nanotechnology.