Beyond Global Charge: Role of Amine Bulkiness and Protein Fingerprint on Nanoparticle–Cell Interaction

Abstract Amino groups presented on the surface of nanoparticles are well‐known to be a predominant factor in the formation of the protein corona and subsequent cellular uptake. However, the molecular mechanism underpinning this relationship is poorly defined. This study investigates how amine type and density affect the protein corona and cellular association of gold nanoparticles with cells in vitro. Four specific poly(vinyl alcohol‐co‐N‐vinylamine) copolymers are synthesized containing primary, secondary, or tertiary amines. Particle cellular association (i.e., cellular uptake and surface adsorption), as well as protein corona composition, are then investigated. It is found that the protein corona (as a consequence of “amine bulkiness”) and amine density are both important in dictating cellular association. By evaluating the nanoparticle surface chemistry and the protein fingerprint, proteins that are significant in mediating particle–cell association are identified. In particular, primary amines, when exposed on the polymer side chain, are strongly correlated with the presence of alpha‐2‐HS‐glycoprotein, and promote nanoparticle cellular association.