Ultrasmall nanoparticles are attracting an increasing interest for a variety of biomedical applications, from therapeutic targeting to imaging, in virtue of the peculiar behavior shown in vivo (i.e., efficient renal clearance, low liver accumulation, etc.). In evaluating their potential to overcome some of the challenges that larger particles have faced, it is important to understand their mechanisms of interaction with the cell membrane in relation to the biological environment and their tendency to transiently interact with biomolecules. In this work, the mechanism of cellular uptake across a range of serum concentrations is investigated using 2 nm gold nanoparticles with different surface chemistries as a model. The data suggest that despite their ultrasmall size, for these nanoparticles, internalization occurs via energy-dependent processes, and the surface chemistry could play a key role in determining the modality of the transient protein interaction, especially in conditions close to the in vivo scenario (large excess of the protein content). These aspects might be exploited to define novel targeting strategies.
Keywords: cellular uptake; gold nanoparticles; nanobio interactions; protein corona; ultrasmall nanoparticles.