Unexpected Size Effect: The Interplay between Different-Sized Nanoparticles in Their Cellular Uptake

The size effect on the cellular uptake of nanoparticles (NPs) has been extensively studied, but it is still not well understood. Herein, a reductionist approach is used to minimize all influencing factors except the particle size, and co-exposure of different-sized silica nanoparticles (SNPs) is adopted instead of the common single exposure. SNPs are found being internalized by Hela cells in serum-free medium mainly via clathrin-dependent endocytosis, thus simplifying the data analysis for reliable attribution to size effects. Remarkably, even though at conditions that the size effects seem very small or even undetectable in the common single exposure experiments, the co-exposure experiments reveal significant size effects due to an unexpected interplay between two different-sized SNPs. Namely, the bigger SNPs significantly promote the cellular uptake of the smaller ones, while the smaller SNPs inhibit the internalization of the bigger ones, with a total uptake increase of the particle number of SNPs in the cells. This strong interplay between different-sized NPs might unavoidably exist within most "single-sized" NP products, whose sizes actually distribute in certain ranges, thus urging reconsideration of the size effect on the cellular uptake of NPs, for the benefits of both bioapplications and safety assessment of nanomaterials.