Polyglycerol Grafting Shields Nanoparticles from Protein Corona Formation to Avoid Macrophage Uptake

Upon contact with biofluids, proteins are quickly adsorbed onto the nanoparticle (NP) surface to form a protein corona, which initiates the opsonization and facilitates the rapid clearance of the NP by macrophage uptake. Although polyethylene glycol (PEG) functionalization has been the standard approach to evade macrophage uptake by reducing protein adsorption, it cannot fully eliminate nonspecific uptake. Herein, polyglycerol (PG) grafting is demonstrated as a better alternative to PEG. NPs of various size and material were grafted with PG and PEG at 30, 20, and 10 wt % contents by controlling the reaction conditions, and the resulting NP-PG and NP-PEG were characterized qualitatively by IR spectroscopy and quantitatively by thermogravimetric analysis. Their resistivity to adsorption of the proteins in fetal bovine serum and human plasma were compared by polyacrylamide gel electrophoresis, bicinchoninic acid assay, and liquid chromatography-tandem mass spectrometry, giving a consistent conclusion that PG shields protein adsorption more efficiently than does PEG. The macrophage uptake was assayed by transmission electron microscopy and by extinction spectroscopy or inductively coupled plasma mass spectrometry, revealing that PG avoids macrophage uptake more efficiently than does PEG. In particular, a NP coated with PG at 30 wt % (NP-PG- h ) prevents corona formation almost completely, regardless of NP size and core material, leading to the complete evasion of macrophage uptake. Our findings demonstrate that PG grafting is a promising strategy in nanomedicine to improve anti-biofouling property and stealth efficiency in nanoformulations.