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

Authors: Zhan Y, Song Y, Qiao W, Sun L, Wang X, Yi B, Yang X, Ji L, Su P, Zhao W, Liu Z, Ren W

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 m<sup>6</sup>A 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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate whether focused ultrasound enhances delivery of mesenchymal stem cell-derived exosomes carrying miR-1208 across the blood–brain barrier to suppress glioma and to elucidate the underlying molecular mechanism.

Animal model / Human subject Mouse, BALB/c nude, 6 weeks old, female

Disease model glioma

Targeted brain region(s) Striatum

Cargo name and characteristics miR-1208 (tumor-suppressor microRNA) delivered via mesenchymal stem cell-derived exosomes (extracellular vesicle/nanoparticle delivery vehicle)

Outcomes and Safety

Summary of Outcomes MSC-derived exosomes loaded with miR-1208 combined with focused ultrasound (FUS) enhanced BBB crossing and uptake by glioma cells, producing potent tumor-suppressive effects in vitro and in xenograft models. Mechanistically, miR-1208 downregulated METTL3, reducing m6A methylation and stability of NUP214 mRNA, lowering NUP214 expression and suppressing TGF-β signaling

Safety-related matter The paper states that exosomes can "safely and effectively" deliver therapeutic substances to glioma cells; no adverse effects or safety concerns are reported in the provided text.

Brain Region

Ultrasound Parameters

Ultrasound instrument Low-power focused ultrasound experiment device

FUS Frequency 650 kHz

FUS Intensity 0.5 W

Duration of a single FUS session 30 s

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency Single session

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