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Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo

Nature Nanotechnology volume 12, pages 387–393 (2017)Cite this article

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Abstract

When nanoparticles are intravenously injected into the body, complement proteins deposit on the surface of nanoparticles in a process called opsonization. These proteins prime the particle for removal by immune cells and may contribute toward infusion-related adverse effects such as allergic responses. The ways complement proteins assemble on nanoparticles have remained unclear. Here, we show that dextran-coated superparamagnetic iron oxide core-shell nanoworms incubated in human serum and plasma are rapidly opsonized with the third complement component (C3) via the alternative pathway. Serum and plasma proteins bound to the nanoworms are mostly intercalated into the nanoworm shell. We show that C3 covalently binds to these absorbed proteins rather than the dextran shell and the protein-bound C3 undergoes dynamic exchange in vitro. Surface-bound proteins accelerate the assembly of the complement components of the alternative pathway on the nanoworm surface. When nanoworms pre-coated with human plasma were injected into mice, C3 and other adsorbed proteins undergo rapid loss. Our results provide important insight into dynamics of protein adsorption and complement opsonization of nanomedicines.

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Figure 1: Complement activation and immune uptake of SPIO nanoworms in human serum and plasma.
Figure 2: Spatial relationship between complement factors, protein corona and core–shell structure.
Figure 3: Mechanism of C3 binding to nanoparticles.
Figure 4: Role of serum protein corona in binding of complement AP factors to SPIO nanoworms.
Figure 5: Dynamic behaviour of C3 opsonization in vitro.
Figure 6: Dynamic behaviour of complement opsonization and protein absorption in vivo.

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Acknowledgements

The study was funded by the University of Colorado Denver start-up funding and NIH 1R01EB022040 to D.S. F.C. was supported by the International Postdoctoral Exchange Fellowship Program (2013) from China Postdoctoral Council. Molecular modelling studies were conducted at the University of Colorado Computational Chemistry and Biology Core Facility, which is supported in part by NIH/NCATS Colorado CTSA grant no. UL1 TR001082. S.M.M. acknowledges financial support by the Danish Agency for Science, Technology and Innovation (Det Strategiske Forskningsråd), reference 09-065746, and Technology and Production, reference 12-126894.

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  1. Fangfang Chen and Guankui Wang: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun, 130033, Jilin, China

    Fangfang Chen

  2. Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado, 80045, USA

    Fangfang Chen, Guankui Wang, James I. Griffin, Barbara Brenneman & Dmitri Simberg

  3. Division of Rheumatology, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, 1775 Aurora Court, Aurora, 80045, Colorado, USA

    Nirmal K. Banda & V. Michael Holers

  4. Department of Pharmaceutical Sciences, Computational Chemistry and Biology Core Facility, the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Boulevard, Aurora, 80045, Colorado, USA

    Donald S. Backos

  5. Department of Pharmacy, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, Universitetsparken 2, University of Copenhagen, Copenhagen, DK-2100, Denmark

    LinPing Wu & Seyed Moein Moghimi

  6. NanoScience Centre, University of Copenhagen, Copenhagen, DK-2100, Denmark

    Seyed Moein Moghimi

  7. School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees, TS17 6BH, UK

    Seyed Moein Moghimi

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Contributions

F.C., G.W., J.I.G., B.B. and L.W. performed the experiments. D.S.B. performed complement modelling. S.M.M., N.K.B., V.M.H. and D.S. analysed the data and edited the manuscript. N.K.B. and V.M.H. provided critical reagents. S.M.M. and D.S. wrote the manuscript.

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Correspondence to Dmitri Simberg.

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Chen, F., Wang, G., Griffin, J. et al. Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo. Nature Nanotech 12, 387–393 (2017). https://doi.org/10.1038/nnano.2016.269

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