Reversible Control Of Protein Corona Formation On Gold Nanoparticles Using Host-Guest Interactions (Vol 14, Pg 5382, 2020)

When nanoparticles (NPs) are exposed to biological media proteins are adsorbed, forming a so-called protein corona (PC). This cloud of protein aggregates hampers the targeting and transport capabilities of the NPs, thereby compromising their biomedical applications. Therefore, there is a high interest in the development of technologies that allow to control the PC formation, as this would provide a handle to manipulate NPs in biological fluids. We present a strategy that enables the reversible disruption of the PC using external stimuli, thereby allowing a precise regulation of NP cellular uptake. The approach, demonstrated for gold nanoparticles, is based on a biorthogonal, supramolecular host-guest interaction between an anionic dye bound to the Au NP surface and a positively charged macromolecular cage. This supramolecular complex effectively behaves as a zwitterionic NP ligand, which is able not only to prevent PC formation, but also to disrupt a previously formed hard corona. Using this supramolecular stimulus, the cellular internalization of Au NPs can be enhanced by up to 30-fold in some cases and even NP cellular uptake in phagocytic cells can be regulated. We additionally prove that the conditional cell uptake of purposely designed gold nanorods can be used to selectively enhance photothermal cell death.