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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

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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.

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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.

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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.

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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

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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.

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The authors declare no competing interests.

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

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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.

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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

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