Modulation of cell uptake and cytotoxicity by nanoparticles with various physicochemical properties after humic acid adsorptionElectronic supplementary information (ESI) available: Continuous processes of humic acid adsorption on different nanoparticles and its effect on nanoparticle binding to the cell membrane. See DOI: 10.1039/d1en00773d

Nanoparticles may acquire coatings of ecological molecules to form an eco–nano interface, which may alter the nature of nano–bio interactions. However, whether the nascent nanoparticle properties are concealed by this eco-corona or still play a role in nano–bio interactions remains unclear. Here, we employ nanoparticles of the same core material, shape and size, but with diverse physicochemical properties to study interplays between nanoparticle properties, adsorption of humic acids (HAs), and downstream interactions with cells. Among nanoparticles, hydrophobic and positively charged nanoparticles are more active in cell uptake and cytotoxicity induction. Although HAs alleviate some nanoparticle uptake and toxicity, the modified activities are still much higher than those of hydrophilic and negatively charged nanoparticles. The latter two nanoparticles are less capable of adsorbing HAs or binding to the cell membrane, as revealed by both experiments and molecular dynamics simulations. Depending on the nanoparticle properties, adsorbed HAs adopt distinct conformations with specific groups exposed to modify the nanoparticle surface properties and influence subsequent interactions with cells. Moreover, HA molecules undergo frequent exchanges allowing exposure of the original nanoparticle surface for cell recognition, explaining the high bioactivities of hydrophobic and positively charged nanoparticles even after heavy HA adsorption. These results demonstrate from the molecular scale that the original nanoparticle surface properties regulate nanoparticle–cell interactions through dictating HA adsorption and conformation or dynamics of HA molecules on the nanoparticle surface, and this critical nanoparticle property cannot be concealed by eco-corona formation.