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.