Although systemically applied nanoparticles are quickly taken up by phagocytic cells, mainly macrophages, the interactions between engineered nanoparticles and macrophages are still not well defined. We therefore analyzed the uptake of diagnostically used carboxydextran-coated superparamagnetic ironoxidenanoparticles of 60 nm (SPIO) and 20 nm (USPIO) by humanmacrophages. By pharmacological and in vitro knockdown approaches, the principal uptake mechanism for both particles was identified as clathrin-mediated, scavenger receptor A-dependent endocytosis. We developed a mathematical model of the uptake process that allows determination of key parameters of endocytosis, including the rate of uptake, the number of nanoparticles per cell in saturation, the mean uptake time, and the correlation between the number of internalized nanoparticles and their extracellular concentration. The calculated parameters correlate well with experimental data obtained by confocal microscopy. Moreover, the model predicts the individual and collective wrapping times of different nanoparticles, describes the relation between cytoskeletal forces, membrane ela ... mehrsticity and the uptake time. We also introduced a new physical parameter á governing the collective uptake process, a reflecting minimal linear spacing between simultaneously acting neighboring endocytotic pits.