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Focused ultrasound combined with miR-1208-equipped exosomes inhibits malignant progression of glioma

British Journal of Cancer volume 129, pages 1083–1094 (2023)Cite this article

Subjects

Abstract

Background

Exosomes (Exos) can safely and effectively deliver therapeutic substances to glioma cells; however, their blood–brain barrier (BBB) crossing capacity remains limited. Focused ultrasound (FUS) can transiently, reversibly, and locally open the BBB, while the effects of FUS combined with Exos-miRNA on the treatment of glioma have not been explored to date.

Methods

Exos were extracted by differential centrifugation and the efficacy of miR-1208-loaded Exos combined with FUS in the treatment of glioma was detected by CCK-8, colony formation, flow cytometry, transwell and tumour xenografts assays. The METTL3-mediated regulation of IGF2BP2 on mRNA stability of NUP214 was determined by MeRIP-qPCR, half-life and RIP assays.

Results

We used Exos secreted by mesenchymal stem cells as carriers for the tumour suppressor gene miR-1208, and following FUS irradiation, more Exos carrying miR-1208 were allowed to pass through the BBB, and the uptake of miR-1208 in Exos by glioma cells was promoted, thereby achieving high-efficiency tumour-suppressive effects. Furthermore, the molecular mechanism underlying this effect was elucidated that miR-1208 downregulated the m6A methylation level of NUP214 mRNA by negatively regulating the expression of METTL3, thereby NUP214 expression and TGF-β pathway activity were suppressed.

Conclusions

MiR-1208-loaded Exos combined with FUS is expected to become an effective glioma treatment and deserves further clinical evaluation.

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Fig. 1: miR-1208 exerts as a tumour suppressor gene in glioma.
Fig. 2: FUS promotes uptake of miR-1208 in Exos by glioma cells.
Fig. 3: Exos-miR-1208 combined with FUS exerts tumour suppressor effects in vivo.
Fig. 4: miR-1208 targets and negatively regulates METTL3 expression.
Fig. 5: METTL3 mediates NUP214 mRNA m6A and promotes NUP214 expression.
Fig. 6: In vivo study.
Fig. 7: Schematic diagram.

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Data availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work is supported by grants from the Natural Science Foundation of China (81571686), Natural Science Foundation of Liaoning Province (2020-MS-170), Basic Scientific Research Project of Colleges and Universities of Liaoning Province (LJKMZ20221148), Science and Technology Plan of Shenyang City (22-321-33-18) and Outstanding Scientific Research Talent Plan of Shengjing hospital (No. 2020M0322).

Author information

Author notes

  1. These authors contributed equally: Ying Zhan, Yichen Song.

Authors and Affiliations

  1. Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Ying Zhan, Wei Qiao, Lu Sun, Xin Wang, Zhijun Liu & Weidong Ren

  2. Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Yichen Song, Bolong Yi, Xinyu Yang & Wujun Zhao

  3. Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China

    Yichen Song, Bolong Yi, Xinyu Yang & Wujun Zhao

  4. Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China

    Yichen Song, Bolong Yi, Xinyu Yang & Wujun Zhao

  5. Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Lian Ji & Peng Su

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Contributions

WR contributed to the experiment design and implementation, manuscript draft, and data analysis. YZ contributed to the experiment implementation and data analysis. YS, WQ, BY, LJ, PS and LS performed the experiments. ZL, WZ, XW, and XY analysed the data. YZ, YS and ZL conceived or designed the experiments, performed the experiments and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Weidong Ren.

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The authors declare no competing interests.

Ethical approval

All clinical specimens used in this study were approved by the Ethics Committee of the Shengjing Hospital of China Medical University. All animal experiments were approved by the Laboratory Animal Management Committee of Shengjing Hospital of China Medical University.

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Zhan, Y., Song, Y., Qiao, W. et al. Focused ultrasound combined with miR-1208-equipped exosomes inhibits malignant progression of glioma. Br J Cancer 129, 1083–1094 (2023). https://doi.org/10.1038/s41416-023-02393-w

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