Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation

Abstract

The chemical composition, size, shape and surface characteristics of nanoparticles affect the way proteins bind to these particles, and this in turn influences the way in which nanoparticles interact with cells and tissues1,2,3,4,5. Nanomaterials bound with proteins can result in physiological and pathological changes, including macrophage uptake1,6, blood coagulation7, protein aggregation8 and complement activation7,9, but the mechanisms that lead to these changes remain poorly understood. Here, we show that negatively charged poly(acrylic acid)-conjugated gold nanoparticles bind to and induce unfolding of fibrinogen, which promotes interaction with the integrin receptor, Mac-1. Activation of this receptor increases the NF-κB signalling pathway, resulting in the release of inflammatory cytokines. However, not all nanoparticles that bind to fibrinogen demonstrated this effect. Our results show that the binding of certain nanoparticles to fibrinogen in plasma offers an alternative mechanism to the more commonly described role of oxidative stress in the inflammatory response to nanomaterials.

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Figure 1: Fibrinogen is the major human plasma protein bound by PAA–GNP.
Figure 2: Selective binding of fibrinogen/PAA–GNP complexes to Mac-1 receptors.
Figure 3: Pro-inflammatory effects of fibrinogen/PAA–GNP complexes.
Figure 4: Effects of nanoparticle surface characteristics on fibrinogen binding.

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Acknowledgements

This work was supported by grants from the Australian Research Council (DP8787331) and the National Health and Medical Research Council (569694).

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Z.J.D. performed all the biological experiments, assisted in designing the biological experiments and co-wrote the manuscript. M.L. synthesized and characterized the nanoparticles. M.M. and I.T. designed the nanoparticle synthesis procedure. R.F.M. conceived and designed the biological studies and co-wrote the manuscript.

Corresponding author

Correspondence to Rodney F. Minchin.

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The authors declare no competing financial interests.

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Deng, Z., Liang, M., Monteiro, M. et al. Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation. Nature Nanotech 6, 39–44 (2011). https://doi.org/10.1038/nnano.2010.250

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