Certain nanomaterials are well-known to interact with cells and tissues in the body, triggering physiological and pathological responses ranging from blood coagulation to protein aggregation. Nanomaterials can also cause general inflammation, but the mechanisms by which these responses come about are poorly understood.

A team led by Rodney Minchin at the University of Queensland in Australia has now revealed how particular polymer-coated gold nanoparticles can trigger inflammation.1 The pathway involved seems to be unrelated to oxidative stress — the mechanism commonly used to explain how nanomaterials cause inflammation in the body.

Fig. 1: Schematic illustration of the part of the fibrinogen protein that triggers inflammation when bound by certain gold nanoparticles© 2011 NPG

The researchers prepared the nanoparticles by grafting poly(acrylic acid) chains onto gold cores, and then studied how they interact with fibrinogen, a key blood protein. Fibrinogen is the precursor protein to the blood clotting agent fibrin, but also plays a secondary role; fibrinogen partly unfolds when binding to certain surfaces, revealing a sequence usually hidden within the protein core. This sequence is known to interact with a receptor called Mac-1, which sets off a cascade of inflammatory responses, including the recruitment of certain white blood cells.

Minchin and colleagues show that the nanoparticles can trigger this partial unfolding behavior. The team tested a variety of metal nanoparticles and found that although several bound to fibrinogen, only the 5 nm poly(acrylic acid)-coated gold nanoparticles (PPA-GNPs) were able to activate Mac-1 and trigger the inflammatory cascade. PPA-GNPs of 20 nm in size failed to bring on the inflammatory response, despite binding to the protein. It therefore seems that only the 5 nm particles bind fibrinogen in such a way that reveals its inflammation-triggering core.

The team explains that uncovering the interaction between fibrinogen and PPA-GNP was unexpected, particularly given that both are negatively charged at physiological pH. Minchin ultimately hopes to understand the general rules that govern what makes certain nanoparticles stick to particular proteins, thereby allowing those interactions to be used deliberately for therapeutic purposes such as drug delivery.

“We are looking at different proteins that bind to different particles depending on their surface characteristics,” says Minchin. “Initially we will try to define what causes high-affinity binding, and then we would like to modify proteins to deliberately target specific nanoparticles to specific cell surface receptors.”