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

• Published in: British journal of cancer 2023-10, Vol.129 (7), p.1083-1094
• Main Authors: Zhan, Ying, Song, Yichen, Qiao, Wei, Sun, Lu, Wang, Xin, Yi, Bolong, Yang, Xinyu, Ji, Lian, Su, Peng, Zhao, Wujun, Liu, Zhijun, Ren, Weidong
• Format: Article
• Language: English
• Subjects: 631/67/1922; 631/67/395; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain cancer; Cancer Research; Centrifugation; Cholecystokinin; Drug Resistance; Epidemiology; Exosomes; Exosomes - metabolism; Flow cytometry; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - therapy; Glioma cells; Humans; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Methyltransferases; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular Medicine; Molecular modelling; mRNA stability; Oncology; RNA-Binding Proteins - metabolism; Targeted cancer therapy; Transforming growth factor-b; Tumor suppressor genes; Tumors; Ultrasonic imaging; Ultrasound
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-023-02393-w

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 m 6 A 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.