Polyethylene glycol backfilling mitigates the negative impact of the protein corona on nanoparticle cell targeting

In protein-rich environments such as the blood, the formation of a protein corona on receptor-targeting nanoparticles prevents target recognition. As a result, the ability of targeted nanoparticles to selectively bind to diseased cells is drastically inhibited. Backfilling the surface of a targeted nanoparticle with polyethylene glycol (PEG) molecules is demonstrated to reduce the formation of the protein corona and re-establishes specific binding. The length of the backfilled PEG molecules must be less than the length of the ligand linker; otherwise, PEG interferes with the binding of the targeting ligand to its corresponding cellular receptor. The long and short of it: The adsorption of serum proteins (colored knots) onto targeted nanoparticles (orange circles) can lead to nonspecific cell binding (solid red arrows). Polyethylene glycol (PEG; grey curves) can be used to prevent this; however, long PEG chains can disrupt specific target binding. Shorter PEG chains prevent nonspecific binding without interfering with target recognition (solid green arrow).