Enhancing lipid nanoparticles-mediated RNA delivery to glioblastoma via targeted strategies.

Glioblastoma (GBM) is an aggressive central nervous system (CNS) malignancy with a poor prognosis and limited responses to conventional therapies. RNA-based therapeutics, with their gene-targeting specificity, present a promising avenue for GBM treatment. However, their clinical translation is hampered by several challenges, including inadequate blood-brain barrier (BBB) penetration, RNA instability, and inefficient delivery mechanisms. Lipid nanoparticles (LNPs) have emerged as superior RNA delivery vehicles due to their excellent biocompatibility, tunable structure, and high RNA encapsulation efficiency. This review explores the potential of LNPs for GBM-targeted RNA delivery, highlighting recent advances in LNP formulation optimization, including lipid composition, surface ligand modifications, and stimuli-responsive designs. Furthermore, we examine various delivery routes-such as intranasal and intra-arterial-and advanced physical delivery technologies, including convection-enhanced delivery (CED) and focused ultrasound (FUS), that could be adopted to improve LNP-mediated RNA delivery to GBM. We also discuss the application of LNP-based gene therapeutics, particularly in combination with chemotherapy and immunotherapy, as a promising strategy to improve GBM treatment outcomes. Finally, we introduce the integration of artificial intelligence (AI) in the development of LNPs, with AI-driven, patient-specific delivery systems poised to drive the next generation of precision RNA therapies for GBM.