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Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles


Deposition of complement factors (opsonization) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonization of superparamagnetic iron oxide (SPIO) nanoworms with the third complement protein (C3) was dependent on the biomolecule corona of the nanoparticles. Here we show that natural antibodies play a critical role in C3 opsonization of SPIO nanoworms and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonization on immunoglobulin binding is almost universal and is observed regardless of the complement activation pathway. Only a few surface-bound immunoglobulin molecules are needed to trigger complement activation and opsonization. Although the total amount of plasma proteins adsorbed on nanoparticles does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonization, and may determine individual complement responses to nanomedicines.

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Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD011781. The raw data that support the graphs in Figs. 1c,d,e,g,h,i; 2c,d,e,f; 3c,d,e,f,i,j,k,l; and 5d are available in extended Supplementary Information. Any additional data and data analysis scripts for R are available from L.S. upon request.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 22 January 2019

    In the version of this Article originally published, a technical error led to Fig. 1a containing ‘!!!!!!!!’ above the scale bar. This has now been corrected in all versions of the Article.


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The study was funded by the National Institutes of Health grants EB022040, CA194058, CA174560 to D.S. and Diagnologix, LLC (San Diego, CA) to D.S. F.C. was supported by the International Postdoctoral Exchange Fellowship Program (2013) from China Postdoctoral Council. S.M.M. acknowledges support by International Science and Technology Cooperation of Guangdong Province (reference 2015A050502002), and Guangzhou City (reference 2016201604030050) with RiboBio Co., Ltd., China. The authors thank N. K. Banda and V. M. Holers for their suggestions during this work.

Author information

V.P.V., F.C., H.B., E.V.G., G.B.G. and G.W. performed the experiments. R.S., L.S., S.M.M. and D.S. analysed the data. S.M.M. and D.S. conceived the experiments and wrote the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Dmitri Simberg.

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Fig. 1: Role of immunoglobulins in efficiency of C3 deposition on SPIO nanoworms.
Fig. 2: Role of immunoglobulins in efficiency of C3 deposition on clinically approved SPIO Feraheme.
Fig. 3: Role of immunoglobulins in efficiency of C3 deposition on clinically approved liposomes.
Fig. 4: Association between immunoglobulin and C3 in the protein corona.
Fig. 5: Role of biomolecule corona in C3 and IgG deposition.
Fig. 6: Proposed scheme of the role of biomolecule corona and immunoglobulin in activation of the alternative pathway.