Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
Br J Cancer. 2023 Oct;129(7):1083-1094. doi: 10.1038/s41416-023-02393-w. Epub 2023 Aug 14.
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.
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.
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 mA methylation level of NUP214 mRNA by negatively regulating the expression of METTL3, thereby NUP214 expression and TGF-β pathway activity were suppressed.
MiR-1208-loaded Exos combined with FUS is expected to become an effective glioma treatment and deserves further clinical evaluation.
外泌体 (Exos) 可以安全有效地将治疗物质递送至神经胶质瘤细胞；然而，其血脑屏障 (BBB) 穿透能力仍然有限。聚焦超声 (FUS) 可以瞬时、可逆、局部地打开 BBB，而 FUS 联合 Exos-miRNA 对神经胶质瘤治疗的影响迄今尚未得到探索。
通过差速离心提取 Exos，并通过 CCK-8、集落形成、流式细胞术、Transwell 和肿瘤异种移植实验检测载 miR-1208 的 Exos 联合 FUS 治疗神经胶质瘤的疗效。MeRIP-qPCR、半衰期和 RIP 实验确定 METTL3 介导的 IGF2BP2 对 NUP214 mRNA 稳定性的调节作用。
我们使用间充质干细胞分泌的 Exos 作为肿瘤抑制基因 miR-1208 的载体，经 FUS 照射后，更多携带 miR-1208 的 Exos 可以通过 BBB，促进 miR-1208 在 Exos 中的摄取神经胶质瘤细胞，从而达到高效的肿瘤抑制作用。此外，还阐明了这种作用的分子机制，即 miR-1208 通过负调控 METTL3 的表达下调 NUP214 mRNA 的 mA 甲基化水平，从而抑制 NUP214 的表达和 TGF-β 通路活性。
载 miR-1208 的 Exos 联合 FUS 有望成为一种有效的神经胶质瘤治疗方法，值得进一步临床评估。
