To promote drug delivery to exact sites and cell types, the surface of nanocarriers is functionalized with targeting antibodies or ligands, typically coupled by covalent chemistry. Once the nanocarrier is exposed to biological fluid such as plasma, however, its surface is inevitably covered with various biomolecules forming the protein corona, which masks the targeting ability of the nanoparticle. Here, we show that we can use a pre-adsorption process to attach targeting antibodies to the surface of the nanocarrier. Pre-adsorbed antibodies remain functional and are not completely exchanged or covered by the biomolecular corona, whereas coupled antibodies are more affected by this shielding. We conclude that pre-adsorption is potentially a versatile, efficient and rapid method of attaching targeting moieties to the surface of nanocarriers.

The nature of the protein corona forming on biomaterial surfaces can affect the performance of implanted devices. This study investigated the role of surface chemistry and wettability on human serum-derived protein corona formation on biomaterial surfaces and the subsequent effects on the cellular innate immune response. Plasma polymerization, a substrate-independent technique, was employed to create nanothin coatings with four specific chemical functionalities and a spectrum of surface charges and wettability. The amount and type of protein adsorbed was strongly influenced by surface chemistry and wettability but did not show any dependence on surface charge. An enhanced adsorption of the dysopsonin albumin was observed on hydrophilic carboxyl surfaces while high opsonin IgG2 adsorption was seen on hydrophobic hydrocarbon surfaces. This in turn led to a distinct immune response from macrophages; hydrophilic surfaces drove greater expression of anti-inflammatory cytokines by macrophages, whilst surface hydrophobicity caused increased production of proinflammatory signaling molecules. These findings map out a unique relationship between surface chemistry, hydrophobicity, protein corona formation, and subsequent cellular innate immune responses; the potential outcomes of these studies may be employed to tailor biomaterial surface modifications, to modulate serum protein adsorption and to achieve the desirable innate immune response to implanted biomaterials and devices.

For nanocarriers with low protein affinity, we show that the interaction of nanocarriers with cells is mainly affected by the density, the molecular weight, and the conformation of polyethylene glycol (PEG) chains bound to the nanocarrier surface. We achieve a reduction of nonspecific uptake of ovalbumin nanocarriers by dendritic cells using densely packed PEG chains with a “brush” conformation instead of the collapsed “mushroom” conformation. We also control to a minor extent the dysopsonin adsorption by tailoring the conformation of attached PEG on the nanocarriers. The brush conformation of PEG leads to a stealth behavior of the nanocarriers with inhibited uptake by phagocytic cells, which is a prerequisite for successful in vivo translation of nanomedicine to achieve long blood circulation and targeted delivery. We can clearly correlate the brush conformation of PEG with inhibited phagocytic uptake of the nanocarriers. This study shows that, in addition to the surface’s chemistry, the conformation of polymers controls cellular interactions of the nanocarriers.