Scientific article: Running circles around proteins

Nanoparticles for biomedical and biotechnological applications must remain undetected by the body, which means avoiding binding of proteins from biological fluids such as blood. This challenge remains unsolved for inorganic nanoparticles, such as those used for biomedical imaging. In a study published in ACS Nano, we show that coating particles with cyclic polymers prevents binding of the stickiest and most abundant blood protein, human serum albumin.

When we apply nanoparticles in the biomedical field, they must exhibit low attractive interactions with biomolecules and high stability in complex biological fluids to fulfill their functions. Formation of a protein corona leads to a loss in colloidal stability and clearance in vivo due to aggregation and recognition by the immune system. A well-established strategy to hinder protein adsorption and provide steric stabilization to NPs relies on their functionalization with hydrophilic organic ligands.

The gold standard strategy is to graft a dense brush of linear polymer chains that are strongly hydrated to the nanoparticle's surface. The polymer coating repels proteins that otherwise are strongly attracted to the surface of the core. Despite the solid theory and its many implementations, surprisingly little experimental evidence shows that this approach works by preventing all protein adsorption. Indeed, we and others recently demonstrated that blood serum proteins, primarily albumin, bind even to the best-known designs of polymer brush-coated nanoparticles.

A likely culprit is that defects in the polymer brush coating and the difficulty to reach a sufficiently dense polymer brush close to the particle surface enables a few proteins to build a soft corona around the particle.

We show that the grafting of polymers with no ends, i.e., cyclic polymers, creates the dense polymer shells needed to protect the nanoparticles from protein adsorption. This resulted from a combination of increased grafting density and increased shell density close to the particle surface.

This first of its kind result was found by applying isothermal titration calorimetry to nanoparticle-protein interactions; it is a novel but an extremely sensitive technique for such measurements. The study is published in the highly-ranked journal ACS Nano as “Polymer Topology Determines the Formation of Protein Corona on Core-Shell Nanoparticles”.