Size-Dependent Facilitation of Cancer Cell Targeting by Proteins Adsorbed on Nanoparticles

Understandings of how biomolecules modify nanoparticles in a biological context and how these exchanges impact nano-biointeractions are fundamental to nanomedicine and nanotoxicology research. In this work, cancer-targeting gold nanoparticles (TGNPs) with different sizes (5, 15, and 40 nm) were designed and synthesized. These nanoparticles spontaneously adsorbed proteins in complete cell culture medium (Dulbecco's modified Eagle's medium with 10% human serum). Although the targeting ligands on the surface of nanoparticles were likely to be shielded by adsorbed proteins, the targeting capability of nanoparticles was maintained due to the highly dynamic nature of protein adsorption. By regulating the size and surface curvature of nanoparticles, we found that smaller TGNPs (5 nm, large surface curvature) recognize folate receptors on HeLa cells mainly through one-on-one bindings, and adsorbed proteins partially interfered with their binding, inducing a reduction of cell uptake by ∼30%. Larger TGNPs (40 nm, small surface curvature) bound to cell surface receptors through multivalent interactions, and their binding affinity was, in contrast, enhanced by adsorbed proteins, resulting in an increased cell uptake by ∼13%. Computational modeling further corroborated our experimental findings. The compelling findings from this work demonstrated how nanoparticle's size controlled its biological activity and provided key design principles for nanomedicine agents.