Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase

Nature Nanotechnology volume 16, pages 1150–1160 (2021)Cite this article

Subjects

Abstract

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle’s centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: BPNS treatment causes mitotic delay and aberrant spindle formation.
Fig. 2: Centrosome defects in BPNS-treated cells.
Fig. 3: Lysosome-mediated centrosome towards trafficking of BPNS during cell cycle.
Fig. 4: BPNS treatment suppresses the mitotic activation of PLK1 kinase at centrosomes.
Fig. 5: BPNS directly binds to PLK1 and induces PLK1 aggregation.
Fig. 6: The anticancer activity of BPNS nanomaterial by inhibiting mitotic progression.

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information, and in the Zenodo repository with the identifier https://doi.org/10.5281/zenodo.4765651. Source data are provided with this paper.

References

  1. Kim, B. Y. S., Rutka, J. T. & Chan, W. C. W. Current concepts: nanomedicine. N. Engl. J. Med. 363, 2434–2443 (2010).

    Article  CAS  Google Scholar 

  2. Patra, J. K. et al. Nano based drug delivery systems: recent developments and future prospects. J. Nanobiotechnol. 16, 71 (2018).

    Article  Google Scholar 

  3. Albanese, A., Tang, P. S. & Chan, W. C. W. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 14, 1–16 (2012).

    Article  CAS  Google Scholar 

  4. Tee, J. K. et al. Nanoparticles’ interactions with vasculature in diseases. Chem. Soc. Rev. 48, 5381–5407 (2019).

    Article  CAS  Google Scholar 

  5. Peng, F. et al. Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness. Nat. Nanotechnol. 14, 279–286 (2019).

    Article  CAS  Google Scholar 

  6. Kim, D. et al. Graphene quantum dots prevent alpha-synucleinopathy in Parkinson’s disease. Nat. Nanotechnol. 13, 812–818 (2018).

    Article  CAS  Google Scholar 

  7. Liu, C. et al. Reprogramming of cancer invasiveness and macrophage education via a nanostructured antagonist of the TGFb receptor. Mater. Horiz. 6, 1675–1681 (2019).

    Article  Google Scholar 

  8. Wang, J. P., Zhang, L. Y., Peng, F., Shi, X. H. & Leong, D. T. Targeting endothelial cell junctions with negatively charged gold nanoparticles. Chem. Mater. 30, 3759–3767 (2018).

    Article  CAS  Google Scholar 

  9. Setyawati, M. I. et al. Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE-cadherin. Nat. Commun. 4, 1673 (2013).

    Article  CAS  Google Scholar 

  10. Zhang, X. Q. et al. Interactions of nanomaterials and biological systems: implications to personalized nanomedicine. Adv. Drug Deliv. Rev. 64, 1363–1384 (2012).

    Article  CAS  Google Scholar 

  11. Nel, A. E. et al. Understanding biophysicochemical interactions at the nano–bio interface. Nat. Mater. 8, 543–557 (2009).

    Article  CAS  Google Scholar 

  12. Salvati, A. et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat. Nanotechnol. 8, 137–143 (2013).

    Article  CAS  Google Scholar 

  13. Fadeel, B. et al. Advanced tools for the safety assessment of nanomaterials. Nat. Nanotechnol. 13, 537–543 (2018).

    Article  CAS  Google Scholar 

  14. Vu, V. P. et al. Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles. Nat. Nanotechnol. 14, 260–268 (2019).

    Article  CAS  Google Scholar 

  15. Shi, J. J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).

    Article  CAS  Google Scholar 

  16. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  Google Scholar 

  17. Tran, S., DeGiovanni, P. J., Piel, B. & Rai, P. Cancer nanomedicine: a review of recent success in drug delivery. Clin. Transl. Med. 6, 44 (2017).

    Article  Google Scholar 

  18. Arquint, C., Gabryjonczyk, A. M. & Nigg, E. A. Centrosomes as signalling centres. Philos. Trans. R. Soc. B 369, 20130464 (2014).

    Article  Google Scholar 

  19. Conduit, P. T., Wainman, A. & Raff, J. W. Centrosome function and assembly in animal cells. Nat. Rev. Mol. Cell Biol. 16, 611–624 (2015).

    Article  CAS  Google Scholar 

  20. Azimzadeh, J. & Bornens, M. Structure and duplication of the centrosome. J. Cell Sci. 120, 2139–2142 (2007).

    Article  CAS  Google Scholar 

  21. Nigg, E. A. & Holland, A. J. Once and only once: mechanisms of centriole duplication and their deregulation in disease. Nat. Rev. Mol. Cell Biol. 19, 297–312 (2018).

    Article  CAS  Google Scholar 

  22. Rivera-Rivera, Y. & Saavedra, H. I. Centrosome—a promising anti-cancer target. Biologics 10, 167–176 (2016).

    CAS  Google Scholar 

  23. Yi, Y., Yu, X. F., Zhou, W. H., Wang, J. H. & Chu, P. K. Two-dimensional black phosphonts: synthesis, modification, properties, and applications. Mater. Sci. Eng. R 120, 1–33 (2017).

    Article  Google Scholar 

  24. Sun, Z. B. et al. Ultrasmall black phosphorus quantum dots: synthesis and use as photothermal agents. Angew. Chem. Int. Ed. 54, 11526–11530 (2015).

    Article  CAS  Google Scholar 

  25. Shao, J. D. et al. Biodegradable black phosphorus-based nanospheres for in vivo photothermal cancer therapy. Nat. Commun. 7, 12967 (2016).

    Article  CAS  Google Scholar 

  26. Zhou, W. H. et al. Black phosphorus: bioactive nanomaterials with inherent and selective chemotherapeutic effects. Angew. Chem. Int. Ed. 58, 769–774 (2019).

    Article  CAS  Google Scholar 

  27. Shao, J. D. et al. Black-phosphorus-incorporated hydrogel as a sprayable and biodegradable photothermal platform for postsurgical treatment of cancer. Adv. Sci. 5, 1700848 (2018).

    Article  Google Scholar 

  28. Mahmoudi, M., Azadmanesh, K., Shokrgozar, M. A., Journeay, W. S. & Laurent, S. Effect of nanoparticles on the cell life cycle. Chem. Rev. 111, 3407–3432 (2011).

    Article  CAS  Google Scholar 

  29. AshaRani, P. V., Mun, G. L. K., Hande, M. P. & Valiyaveettil, S. Cytotoxicity and genotoxicity of silver nanoparticles in human cells. Acs Nano 3, 279–290 (2009).

    Article  CAS  Google Scholar 

  30. Musacchio, A. The molecular biology of spindle assembly checkpoint signaling dynamics. Curr. Biol. 25, R1002–R1018 (2015).

    Article  CAS  Google Scholar 

  31. Maiato, H. & Logarinho, E. Mitotic spindle multipolarity without centrosome amplification. Nat. Cell Biol. 16, 386–U323 (2014).

    Article  CAS  Google Scholar 

  32. Saunders, W. Centrosomal amplification and spindle multipolarity in cancer cells. Semin. Cancer Biol. 15, 25–32 (2005).

    Article  CAS  Google Scholar 

  33. Hamalisto, S. et al. Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation. Nat. Commun. 11, 229 (2020).

    Article  CAS  Google Scholar 

  34. Kurz, T., Terman, A., Gustafsson, B. & Brunk, U. T. Lysosomes and oxidative stress in aging and apoptosis. Biochim. Biophys. Acta Gen. Subj. 1780, 1291–1303 (2008).

    Article  CAS  Google Scholar 

  35. Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10, 9–17 (2014).

    Article  CAS  Google Scholar 

  36. Wang, X. Y. & Quinn, P. J. The location and function of vitamin E in membranes (review). Mol. Membr. Biol. 17, 143–156 (2000).

    Article  Google Scholar 

  37. Boya, P. et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 22, 3927–3936 (2003).

    Article  CAS  Google Scholar 

  38. Appelqvist, H. et al. Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation. Am. J. Pathol. 178, 629–639 (2011).

    Article  CAS  Google Scholar 

  39. Aits, S. et al. Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. Autophagy 11, 1408–1424 (2015).

    Article  CAS  Google Scholar 

  40. Wang, G., Jiang, Q. & Zhang, C. M. The role of mitotic kinases in coupling the centrosome cycle with the assembly of the mitotic spindle. J. Cell Sci. 127, 4111–4122 (2014).

    CAS  Google Scholar 

  41. Asteriti, I. A., De Mattia, F. & Guarguaglini, G. Cross-talk between AURKA and Plk1 in mitotic entry and spindle assembly. Front. Oncol. 5, 283 (2015).

    Article  Google Scholar 

  42. Macurek, L. et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 455, 119–U188 (2008).

    Article  CAS  Google Scholar 

  43. Archambault, V. & Glover, D. M. Polo-like kinases: conservation and divergence in their functions and regulation. Nat. Rev. Mol. Cell Biol. 10, 265–275 (2009).

    Article  CAS  Google Scholar 

  44. Mo, J. B., Xie, Q. Y., Wei, W. & Zhao, J. Revealing the immune perturbation of black phosphorus nanomaterials to macrophages by understanding the protein corona. Nat. Commun. 9, 2480 (2018).

    Article  Google Scholar 

  45. Ventola, C. L. Progress in nanomedicine: approved and investigational nanodrugs. P T 42, 742–755 (2017).

    Google Scholar 

  46. Li, S. P. et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nat. Biotechnol. 36, 258–264 (2018).

    Article  CAS  Google Scholar 

  47. Shao, X. M. et al. Numb regulates vesicular docking for homotypic fusion of early endosomes via membrane recruitment of Mon1b. Cell Res. 26, 593–612 (2016).

    Article  CAS  Google Scholar 

  48. Liu, K. et al. Targeting polo-like kinase 1 by a novel pyrrole-imidazole polyamide-Hoechst conjugate suppresses tumor growth in vivo. Mol. Cancer Ther. 17, 988–1002 (2018).

    Article  CAS  Google Scholar 

  49. Mahen, R., Jeyasekharan, A. D., Barry, N. P. & Venkitaraman, A. R. Continuous polo-like kinase 1 activity regulates diffusion to maintain centrosome self-organization during mitosis. Proc. Natl Acad. Sci. USA 108, 9310–9315 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank X. Liu (University of Kentucky, USA) for kindly providing Flag/GFP-PLK1 expression plasmids and anti-pS195-Clip-170 antibody. We also thank D. Boraschi (National Research Council of Italy) for critical reading and revision of the manuscript. This work was supported by grants no. 31871366 (to H.L.) and no. 81870174 (to X.S.) from the National Natural Science Foundation of China; grants no. 2021A1515012114 (to X.S.), no. 2018B030308001 (to H.L.) and no. 2016A030312006 (to L. Cai) from the Natural Science Foundation of Guangdong Province; grants no. JCYJ20200109114608075 (to X.S.), no. RCJC20200714114435061 (to X.-F.Y.), no. GJHZ20190821155803877 (to Yang Li) and no. JCYJ20170818153538196 (to W.Su) from Shenzhen Science and Technology Program; and CAS President’s International Fellowship Initiative (PIFI) 2020VBA0028 (to Yang Li).

Author information

Author notes

  1. These authors contributed equally: Ximing Shao, Zhihao Ding.

Authors and Affiliations

  1. Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Ximing Shao, Zhihao Ding, Wenhua Zhou, Yanyan Li, Zhibin Li, Haodong Cui, Xian Lin, Guoli Cao, Binghua Cheng, Haiyan Sun, Meiqing Li, Ke Liu, Danyi Lu, Shengyong Geng, Wenli Shi, Guofang Zhang, Qingle Song, Liang Chen, Guocheng Wang, Wu Su, Lintao Cai, Lijing Fang, Yang Li, Xue-Feng Yu & Hongchang Li

  2. Guangdong Key Laboratory of Nanomedicine, Shenzhen, China

    Ximing Shao, Zhihao Ding, Ke Liu, Lintao Cai & Hongchang Li

  3. University of Chinese Academy of Sciences, Beijing, China

    Yanyan Li, Binghua Cheng & Meiqing Li

  4. Hainan University, Haikou, China

    Wenli Shi

  5. Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Singapore

    David Tai Leong

  6. Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen, China

    Hongchang Li

Authors
  1. Ximing Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhihao Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenhua Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanyan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhibin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haodong Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xian Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guoli Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Binghua Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Haiyan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Meiqing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ke Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Danyi Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shengyong Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Wenli Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Guofang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Qingle Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Liang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Guocheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Wu Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Lintao Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Lijing Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. David Tai Leong
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Xue-Feng Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Hongchang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.L., X.-F.Y. and Yang Li conceived the project and supervised the study. X.S. and Z.D. performed most cell biological, biochemical and animal experiments. W.Z., Z.L., H.C., Q.S. and G.W. prepared and characterized the nanomaterials. S.G. prepared the liposomes. B.C. and M.L. assisted with biochemical and animal experiments. Yanyan Li performed the FRAP assay. H.S., X.L. and K.L. performed live-cell imaging. Yanyan Li, X.L., W. Shi, G.C., D.L. and G.Z. participated in cell culture and immunofluorescence staining. X.S., W.Z., L. Chen, W.Su, L.F., L. Cai, D.T.L., Yang Li and X.-F.Y. discussed the data. X.S., W.Z., D.T.L., Yang Li, X.-F.Y. and H.L. wrote the manuscript.

Corresponding authors

Correspondence to Yang Li, Xue-Feng Yu or Hongchang Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Nanotechnology thanks Matteo Goldoni and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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

Supplementary information

Supplementary Information

Supplementary Figs. 1–27, unprocessed gel/blots for supplementary figures, discussion and refs. 1–20.

Reporting Summary

Supplementary Video 1

A representative live-cell movie of control HeLa cells undergoing mitosis.

Supplementary Video 2

A representative live-cell movie of BPNS-treated HeLa cells undergoing mitosis.

Supplementary Video 3

A representative live-cell movie of BPNS-treated HeLa cells undergoing apoptosis after cell division.

Source data

Source Data Fig. 4

Unprocessed western blots.

Source Data Fig. 5

Unprocessed western blots.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shao, X., Ding, Z., Zhou, W. et al. Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase. Nat. Nanotechnol. 16, 1150–1160 (2021). https://doi.org/10.1038/s41565-021-00952-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41565-021-00952-x

This article is cited by

Search

Advanced search

Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research