The cellular uptake efficiency of nanostructures has been demonstrated to be highly dependent on the surface charge, size and shape although the cellular internalization process is still far from being well-understood. In this work, a series of NaYF4:Yb3+, Er3+ upconversion nanoparticles (UCNPs) with different morphologies and surface coatings were prepared to explore the influence of surface charge and morphology on the cellular internalization process with single-particle fluorescence microscopy. It is found that the higher the surface charge and larger the surface-to-volume ratio of the nanoparticles, the more efficient the cellular uptake will be. Particularly, the surface charge is demonstrated to be the primary influence factor for small sized nanoparticles on the cellular uptake process. By blocking the endocytosis routes with temperature modulation (from 37 to 4 °C) or introduction of chemical inhibitors (dynasore and genistein), multiplexed mechanisms are found to be involved in the cellular uptake process, including clathrin- and caveolae-mediated endocytosis, physical adhesion and penetration, and so on. Moreover, in the aspect of size effect, an energy-dependent endocytosis process plays a more important role for larger size particles. In short, this study presents a pattern of cellular internalization pathway for the nanoparticles with different morphologies and surface charges, which would provide useful information for the development of robust drug delivery systems.
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