外泌体（Exos）能够安全有效地将治疗物质传递给胶质瘤细胞；然而，它们穿越血脑屏障（BBB）的能力仍然有限。聚焦超声（FUS）可以短暂、可逆地和局部地打开BBB，但迄今为止尚未探究FUS与Exos-miRNA联合治疗胶质瘤的效果。通过差速离心提取了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了miR-1208载荷的Exos与FUS联合治疗胶质瘤的疗效。通过MeRIP-qPCR、半衰期和RIP实验确定了METTL3介导的IGF2BP2对NUP214 mRNA稳定性的调控。我们使用间充质干细胞分泌的Exos作为抑制肿瘤基因miR-1208的载体，在FUS照射后，更多携带miR-1208的Exos能够穿过BBB，促进胶质瘤细胞对miR-1208的摄取，从而实现高效的抑制肿瘤效果。此外，揭示了这一效应的分子机制，即miR-1208通过负调控METTL3表达，降低了NUP214 mRNA的m6A甲基化水平，从而抑制了NUP214的表达和TGF-β通路的活性。miR-1208载荷的Exos与FUS的联合治疗有望成为一种有效的胶质瘤治疗方法，并值得进一步的临床评估。© 2023年作者，在Springer Nature Limited的独家许可下。

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 m6A 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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.