Precision RNA-based Gene Silencing and Theranostics Delivery Strategies for Glioma: Advances in siRNA and Emerging miRNA Therapeutics.

INTRODUCTION: Gliomas, particularly Glioblastoma Multiforme (GBM), remain highly lethal despite surgery, radiotherapy, and chemotherapy, largely due to their infiltrative biology, marked molecular heterogeneity, and the restrictive Blood-Brain Barrier. RNA interference (RNAi)-based therapeutics, including Small Interfering RNA (siRNA) and emerging microRNA (miRNA)-modulating strategies, enable targeted silencing of oncogenic drivers. However, their clinical application is constrained by rapid systemic clearance, nuclease-mediated degradation, off-target effects, and inefficient brain delivery. OBJECTIVE: This review evaluates recent advances in RNA-based precision gene silencing for glioma, with particular focus on siRNA therapeutics, emerging miRNA strategies, nanocarrier-enabled delivery systems, and theranostic integration for imaging-guided therapy. METHOD: A comprehensive literature search (1998-2026) of PubMed, Scopus, and Google Scholar was performed to identify preclinical and early clinical studies addressing glioma pathobiology, RNA interference mechanisms, siRNA targets, nanocarrier platforms, and imaging-guided theranostic systems, with emphasis on orthotopic models, registered clinical trials, and mechanistically well-characterized datasets. RESULTS: Non-viral nanocarriers (lipid nanoparticles, bio-reducible polymers, dendrimer-gold, exosomes) enable siRNA protection, BBB penetration, and knockdown of EGFR, STAT3, BCL-2, VEGF, and GLUT-3 in orthotopic glioma models. Emerging miRNA-based strategies, including anti-miR-21 and miR-100 modulation, showed potential for reversing chemoresistance. Combination therapies with temozolomide/doxorubicin produced greater efficacy than single-agent approaches. Theranostic imaging platforms (PET/MRI/SPECT) enabled real-time monitoring of biodistribution and treatment responses. CONCLUSION: RNA-based theranostic strategies show promising potential for glioma therapy. However, further optimization of delivery systems, improved safety profiles, and successful clinical translation remain necessary.