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Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis

Nature Nanotechnology volume 13, pages 1182–1190 (2018)Cite this article

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Abstract

Rheumatoid arthritis is a common chronic inflammatory disorder and a major cause of disability. Despite the progress made with recent clinical use of anti-cytokine biologics, the response rate of rheumatoid arthritis treatment remains unsatisfactory, owing largely to the complexity of cytokine interactions and the multiplicity of cytokine targets. Here, we show a nanoparticle-based broad-spectrum anti-inflammatory strategy for rheumatoid arthritis management. By fusing neutrophil membrane onto polymeric cores, we prepare neutrophil membrane-coated nanoparticles that inherit the antigenic exterior and associated membrane functions of the source cells, which makes them ideal decoys of neutrophil-targeted biological molecules. It is shown that these nanoparticles can neutralize proinflammatory cytokines, suppress synovial inflammation, target deep into the cartilage matrix, and provide strong chondroprotection against joint damage. In a mouse model of collagen-induced arthritis and a human transgenic mouse model of arthritis, the neutrophil membrane-coated nanoparticles show significant therapeutic efficacy by ameliorating joint damage and suppressing overall arthritis severity.

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Fig. 1: Preparation and characterization of neutrophil-NPs.
Fig. 2: Neutrophil-NPs inhibit pro-arthritogenic factors in vitro.
Fig. 3: Neutrophil-NPs enhance cartilage penetration and confer chondroprotection.
Fig. 4: Neutrophil-NPs ameliorate joint destruction in a mouse model of collagen-induced arthritis and a human transgenic mouse model of inflammatory arthritis.
Fig. 5: Neutrophil-NPs ameliorate joint destruction and elicit a systemic therapeutic response following a prophylactic regimen.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

References

  1. Smolen, J. S. & Aletaha, D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat. Rev. Rheumatol. 11, 276–289 (2015).

    Article  Google Scholar 

  2. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    Article  CAS  Google Scholar 

  3. Firestein, G. S. & McInnes, I. B. Immunopathogenesis of rheumatoid arthritis. Immunity 46, 183–196 (2017).

    Article  CAS  Google Scholar 

  4. Burmester, G. R., Feist, E. & Doerner, T. Emerging cell and cytokine targets in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 77–88 (2014).

    Article  CAS  Google Scholar 

  5. Goulielmos, G. N. et al. Genetic data: the new challenge of personalized medicine, insights for rheumatoid arthritis patients. Gene 583, 90–101 (2016).

    Article  CAS  Google Scholar 

  6. McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol. 7, 429–442 (2007).

    Article  CAS  Google Scholar 

  7. Noack, M. & Miossec, P. Selected cytokine pathways in rheumatoid arthritis. Semin. Immunopathol. 39, 365–383 (2017).

    Article  CAS  Google Scholar 

  8. Choy, E. H. S. & Panayi, G. S. Mechanisms of disease: cytokine pathways and joint inflammation in rheumatoid arthritis. New Engl. J. Med. 344, 907–916 (2001).

    Article  CAS  Google Scholar 

  9. Smolen, J. S. et al. New therapies for treatment of rheumatoid arthritis. Lancet 370, 1861–1874 (2007).

    Article  CAS  Google Scholar 

  10. Bykerk, V. Unmet needs in rheumatoid arthritis. J. Rheumatol. 36, 42–46 (2009).

    Article  Google Scholar 

  11. Taylor, P. C. et al. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol. Int. 36, 685–695 (2016).

    Article  CAS  Google Scholar 

  12. Iwata, S. & Tanaka, Y. Progress in understanding the safety and efficacy of janus kinase inhibitors for treatment of rheumatoid arthritis. Exp. Rev. Clin. Immunol. 12, 1047–1057 (2016).

    Article  CAS  Google Scholar 

  13. Smolen, J. S. et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann. Rheum. Dis. 75, 3–15 (2016).

    Article  Google Scholar 

  14. Hu, C. M. J. et al. A biomimetic nanosponge that absorbs pore-forming toxins. Nat. Nanotech. 8, 336–340 (2013).

    Article  CAS  Google Scholar 

  15. Hu, C. M. J. et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 526, 118–121 (2015).

    Article  CAS  Google Scholar 

  16. Copp, J. A. et al. Clearance of pathological antibodies using biomimetic nanoparticles. Proc. Natl Acad. Sci. USA 111, 13481–13486 (2014).

    Article  CAS  Google Scholar 

  17. Thamphiwatana, S. et al. Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management. Proc. Natl Acad. Sci. USA 114, 11488–11493 (2017).

    Article  CAS  Google Scholar 

  18. Tak, P. P. et al. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum. 40, 217–225 (1997).

    Article  CAS  Google Scholar 

  19. Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).

    CAS  Google Scholar 

  20. Dalli, J. et al. Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties. Mol. Cell. Proteomics 12, 2205–2219 (2013).

    Article  CAS  Google Scholar 

  21. Headland, S. E. Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. Sci. Transl. Med. 7, 315ra190 (2015).

    Article  Google Scholar 

  22. Wright, H. L., Moots, R. J. & Edwards, S. W. The multifactorial role of neutrophils in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 593–601 (2014).

    Article  CAS  Google Scholar 

  23. Wipke, B. T. & Allen, P. M. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J. Immunol. 167, 1601–1608 (2001).

    Article  CAS  Google Scholar 

  24. Cedergren, J., Forslund, T., Sundqvist, T. & Skogh, T. Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients. J. Rheumatol. 34, 2162–2170 (2007).

    CAS  Google Scholar 

  25. Chakravarti, A., Raquil, M. A., Tessier, P. & Poubelle, P. E. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood 114, 1633–1644 (2009).

    Article  CAS  Google Scholar 

  26. Wright, H. L., Cox, T., Moots, R. J. & Edwards, S. W. Neutrophil biomarkers predict response to therapy with tumor necrosis factor inhibitors in rheumatoid arthritis. J. Leukocyte Biol. 101, 785–795 (2017).

    Article  CAS  Google Scholar 

  27. Hu, C.-M. J. et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl Acad. Sci. USA 108, 10980–10985 (2011).

    Article  CAS  Google Scholar 

  28. Declerck, L. S. et al. Expression of neutrophil activation markers and neutrophil adhesion to chondrocytes in rheumatoid-arthritis patients—relationship with disease-activity. Res. Immunol. 146, 81–87 (1995).

    Article  CAS  Google Scholar 

  29. Karsten, E., Breen, E. & Herbert, B. R. Red blood cells are dynamic reservoirs of cytokines. Sci. Rep. 8, 3101 (2018).

    Article  Google Scholar 

  30. Brzustewicz, E. et al. Heterogeneity of the cytokinome in undifferentiated arthritis progressing to rheumatoid arthritis and its change in the course of therapy. Move toward personalized medicine. Cytokine 97, 1–13 (2017).

    Article  CAS  Google Scholar 

  31. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  32. Schmidt, E. P. et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat. Med. 18, 1217–1223 (2012).

    Article  CAS  Google Scholar 

  33. Brand, D. D., Latham, K. A. & Rosloniec, E. F. Collagen-induced arthritis. Nat. Protoc. 2, 1269–1275 (2007).

    Article  CAS  Google Scholar 

  34. Williams, R. O., Marinova-Mutafchieva, L., Feldmann, M. & Maini, R. N. Evaluation of TNF-α and IL-1 blockade in collagen-induced arthritis and comparison with combined anti-TNF-α/anti-CD4 therapy. J. Immunol. 165, 7240–7245 (2000).

    Article  CAS  Google Scholar 

  35. Joosten, L. A. B. et al. Il-1αβ blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-α blockade only ameliorates joint inflammation. J. Immunol. 163, 5049–5055 (1999).

    CAS  Google Scholar 

  36. Maia, M. et al. CD248 and its cytoplasmic domain a therapeutic target for arthritis. Arthritis Rheum. 62, 3595–3606 (2010).

    Article  Google Scholar 

  37. Pascual, V. et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J. Exp. Med. 201, 1479–1486 (2005).

    Article  CAS  Google Scholar 

  38. Bartok, B. & Firestein, G. S. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev. 233, 233–255 (2010).

    Article  CAS  Google Scholar 

  39. Li, P. & Schwarz, E. M. The TNF-α transgenic mouse model of inflammatory arthritis. Springer Semin. Immunopathol. 25, 19–33 (2003).

    Article  Google Scholar 

  40. Shealy, D. J. et al. Anti-TNF-α antibody allows healing of joint damage in polyarthritic transgenic mice. Arthritis Res. 4, R7 (2002).

    Article  Google Scholar 

  41. Seeuws, S. et al. A multiparameter approach to monitor disease activity in collagen-induced arthritis. Arthritis Res. Ther. 12, R160 (2010).

    Article  Google Scholar 

  42. Kremer, J. M. et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein ctla4ig. New Engl. J. Med. 349, 1907–1915 (2003).

    Article  CAS  Google Scholar 

  43. Kang, T. et al. Nanoparticles coated with neutrophil membranes can effectively treat cancer metastasis. ACS Nano 11, 1397–1411 (2017).

    Article  CAS  Google Scholar 

  44. Dolati, S. et al. Utilization of nanoparticle technology in rheumatoid arthritis treatment. Biomed. Pharmacother. 80, 30–41 (2016).

    Article  CAS  Google Scholar 

  45. Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).

    Article  CAS  Google Scholar 

  46. Jie, Z. et al. Large-scale ex vivo generation of human neutrophils from cord blood CD34+ cells. PLoS ONE 12, e0180832 (2017).

    Article  Google Scholar 

  47. Feng, Q. et al. Scalable generation of universal platelets from human induced pluripotent stem cells. Stem Cell Rep. 3, 817–831 (2014).

    Article  CAS  Google Scholar 

  48. Graham, J. M. Isolation of human polymorphonuclear leukocytes (granulocytes) from a leukocyte-rich fraction. Sci. World J. 2, 1393–1396 (2002).

    Article  CAS  Google Scholar 

  49. Fang, R. et al. Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery. Nano. Lett. 14, 2181–2188 (2014).

    Article  CAS  Google Scholar 

  50. Luk, B. T. et al. Interfacial interactions between natural RBC membranes and synthetic polymeric nanoparticles. Nanoscale 6, 2730–2737 (2014).

    Article  CAS  Google Scholar 

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Acknowledgements

This work is supported by the Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense under grant no. HDTRA1-14-1-0064 and National Science Foundation grant no. DMR-1505699.

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Authors and Affiliations

  1. Department of NanoEngineering and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    Qiangzhe Zhang, Diana Dehaini, Yue Zhang, Julia Zhou, Xiangyu Chen, Lifen Zhang, Ronnie H. Fang, Weiwei Gao & Liangfang Zhang

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  1. Qiangzhe Zhang
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  2. Diana Dehaini
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Contributions

Lia.Z. conceived and designed the experiments with W.G. and Q.Z. Q.Z., X.C., D.D., Y.Z., J.Z. and Lia.Z. performed all experiments. All authors analysed and discussed the data. Q.Z., W.G., R.H.F. and Lia.Z. wrote the paper.

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Correspondence to Liangfang Zhang.

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Zhang, Q., Dehaini, D., Zhang, Y. et al. Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis. Nature Nanotech 13, 1182–1190 (2018). https://doi.org/10.1038/s41565-018-0254-4

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