Aptamer-guided delivery of miR-126 suppresses glioblastoma stem-like cell invasion and tumor progression

Glioblastoma, IDH-wildtype (GBM) is the most common and aggressive primary brain tumor in adults, with a median overall survival of 15–18 months. New therapeutic targets are needed to improve patients’ prognosis. Due to their powerful regulatory capabilities, miRNAs could be possible candidate targets. MiR-126 is considered a tumor suppressor in several cancers, including GBM. In a previous study, we found that the infiltrative shift observed in response to bevacizumab in a GBM mouse model, induced a high miR-126 downregulation, confirming its tumor-suppressor function, exerted by inhibiting growth and angiogenesis. Here, we either stably restored miR-126 expression in GBM stem-like cells by transduction or transiently delivered it through an A40s aptamer-based conjugate. Both interventions led to an overall impairment of tumorigenic properties. Notably, in vivo systemic treatment with an aptamer-miR-126 chimera significantly reduced brain infiltration in GBM mouse models. Among miR-126 potential targets, we confirmed the essential amino acid transporter LAT1, the transmembrane receptors PLXNB2 and SPRED1 as responsible for miR-126 negative regulation of GBM development. These findings corroborate miR-126 as both a putative prognostic biomarker and a functional tumor-suppressor in GBM, identifying the aptamer-miR126 chimera as a novel potential candidate for a targeted therapeutic approach for more effective GBM management.