Targeting non-coding RNAs to overcome resistance and improving outcomes in glioblastoma

Glioblastoma (GB) remains the most aggressive and treatment-resistant primary brain tumor, characterized by extensive heterogeneity, therapeutic resistance, and dismal prognosis. In this comprehensive review, we aimed to synthesize emerging insights into the roles of non-coding RNAs (ncRNAs)-including microRNAs, long non-coding RNAs, circular RNAs, and PIWI-interacting RNAs-in the regulation of glioblastoma progression, resistance mechanisms, and potential therapeutic strategies. We critically evaluated the molecular functions of ncRNAs in key oncogenic processes such as proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), and immune evasion. Additionally, we reviewed current detection methods, delivery technologies, and clinical trials targeting these ncRNAs. A central goal of this review was to bridge a notable gap in the literature by highlighting underrepresented ncRNA classes such as circRNAs and piRNAs, which exhibit regulatory complexity and potential as biomarkers and therapeutic agents in GB. We further discussed delivery challenges posed by the blood-brain barrier and explored promising nanocarrier and exosome-based approaches to enhance therapeutic targeting. Through curated case studies, we showcased the translational potential of targeting specific ncRNAs to reverse multiple resistance types and improve immunotherapy response. This review provides a consolidated framework for understanding the dynamic role of ncRNAs in glioblastoma and proposes an expanded toolkit for precision oncology approaches. Our findings not only underscore the therapeutic promise of ncRNAs but also call for future investigations into the lesser-known subclasses that could redefine the landscape of GB management.