The functional groups displayed on the surface of nanoparticles (NP) are known to play an important role in NP cellular uptake. However, only a few systematic studies have been reported to address their role, in large part because of the difficulty in regularly varying the number and structure of the functional groups on the NP surface. We employ a bottom-up strategy for the synthesis of water-soluble organic nanoparticles (ONPs) with different sizes and functional groups, using readily available monomers. Utilizing flow cytometry, we measured the HeLa cell uptake efficiency of ONPs that contain side-chains with a different (a) length, (b) number of hydroxyl groups, and (c) number of methyl groups. We have also investigated ONPs with the same functional groups but different sizes. The potential formation and influence of protein corona was examined using the same approach but in the presence of serum. The results demonstrate that under both serum and serum-free conditions the surface-exposed functional groups determine the efficiency of cellular uptake of the particles, and that the trend can be partially predicted by the lipophilicity of the polymeric ONP's repeating units. Also, by using a "masking" strategy, these particles' cellular uptake behavior could be altered conveniently.
Keywords: cellular uptake; lipophilicity; organic nanoparticle; surface functional groups.