Colloidal Stability and Surface Chemistry Are Key Factors for the Composition of the Protein Corona of Inorganic Gold Nanoparticles

To study the influence of colloidal stability on protein corona formation, gold nanoparticles are synthesized with five distinct surface modifications: coating with citric acid, bis(p-sulfonatophenyl)phenylphosphine dihydrate dipotassium salt, thiol-terminated methoxy-polyethylene glycol, dodecylamine-grafted poly(isobutylene-alt-maleic anhydride), and dodecylamine-grafted poly(isobutylene-alt-maleic anhydride) conjugated with polyethylene glycol. The nanoparticles are incubated with serum or bronchoalveolar lavage fluid from C57BL/6 mice (15 min or 24 h) to assess the effect of differential nanoparticle surface presentation on protein corona formation in the air–blood barrier exposure pathway. Proteomic quantification and nanoparticle size measurements are used to assess protein corona formation. We show that surface modification has a clear effect on the size and the composition of the protein corona that is related to the colloidal stability of the studied nanoparticles. Additionally, differences in the composition and size of the protein corona are shown between biological media and duration of exposure, indicating evolution of the corona through this exposure pathway. Consequently, a major determinant of protein corona formation is the colloidal stability of nanoparticles in biological media and chemical or environmental modification of the nanoparticles alters the surface presentation of the functional epitope in vivo. Therefore, the colloidal stability of nanoparticles has a decisive influence on nano–bio interactions.