miRNA interventions serve as 'magic bullets' in the reversal of glioblastoma hallmarks.

microRNAs (miRNAs) are no longer deemed small pieces of RNA "trash" in the human transcriptome but are considered to be master regulators of gene expression that are critical in maintaining cellular homeostasis post-transcriptionally. The concept triggers great interest in studying miRNA dysregulations in human diseases, especially in cancers. Glioblastoma (GBM) has long been the leading cause of the high mortality and morbidity of CNS tumors in adults, which is a consequence of the lack of strategies to reverse the hallmark features of GBM (e.g., borderless expansion and diffuse infiltration). In the past decade, dissecting the molecular architecture of GBM has led to a better understanding of the molecular basis of the hallmarks, generating many promising pharmacological protein targets. However, few clinical responses have been highlighted, suggesting the demand for new therapeutic strategies and targets. In this review, we systemically summarize the context-dependently validated miRNAs with one or more functional targets in the development of GBM hallmarks and review the current miRNA-targeting strategies. We note that only a few miRNA-based therapeutics are trialed for clinical significance, and none of them is tailored to GBM, thereby urging us to bring miRNA therapeutics to the front line either alone or in combination.