The protein coat nanoparticles pick up in human blood could affect their toxicity as well as their medical potential

Polymer nanoparticles suspended in human blood become cloaked in plasma proteins, new research has shown. The composition of the protein cloak depends not only on the surface properties of the nanoparticle, but also, surprisingly, on its size.

The findings suggest that when a nanoparticle enters the blood it soon acquires a new identity based on proteins, and it is these, rather than the nanoparticle per se, that are likely to be recognised at, say, a cell surface. The findings have implications for scientists’ understanding of nanoparticle toxicity, but also on nanoparticle-based targeted therapies.

’If this paradigm is correct, current thinking on how we target nanomedicines may be incomplete,’ says Kenneth Dawson of University College Dublin in Ireland, who led the study. ’It might also explain why the targeting of nanoparticles sometimes does not work well.’

Dawson and his colleagues set out to discover the extent of protein binding to nanoparticles, and then identify the proteins. They experimented with polystyrene particles of 100 and 50nm, with a positive, negative, or neutral surface charge. The team suspended the particles in human blood plasma, removed them after an hour and subjected them to a specially designed washing regime to remove all but the stickiest proteins, referred to as the ’hard corona’. They then removed these proteins, separated them and identified them by mass spectrometry.

’We found that the surface charge of the particle has an effect on the proteins it pulls down onto itself, but what was really surprising was the influence of the size of the particle,’ Dawson says. There was a significantly different protein profile between the two sizes of particle. ’Size matters, and it matters enormously,’ says Dawson.

Protein penumbra

Around 40 plasma proteins typically constitute the ’hard corona’ or crust of proteins on the particle, of which there is usually a hardcore of around ten that are abundant. ’These 40 are not the same on every particle and the top ten can change,’ Dawson says. Intriguingly, apolipoproteins often show up, which are involved in the transport and uptake of molecules into tissues. Proteins of the immune system also attach, as well as those involved in blood clotting.

’What is important is that the particles pick up a highly specific protein identity, and it is not just obvious proteins that bind but very specific ones,’ says Dawson. So the body will ’see’ an agglomeration of proteins rather than a particle of silica or gold or whatever the nanoparticle is made from.

This will be crucial to determining safety issues of nanoparticles if they are to be used in medicine, says Dawson, and also opens a route to tailoring the biological properties of particles by manipulating their size and surface characteristics.

Maya Thanou of Imperial College London,UK, who researches the diffusion of nanoparticles across biological membranes, says, ’The work shows that we can identify how nanoparticles behave in the blood depending on their size and surface properties. We now need a thorough and systematic study of the interaction of nanoparticles with blood proteins to determine their behaviour for nanomedicine applications and any toxicological implications.’

Simon Hadlington

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