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

Nov 29, 2025Journal of controlled release : official journal of the Controlled Release Society

Improving RNA delivery to brain tumors using targeted lipid nanoparticles

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Abstract

Lipid nanoparticles (LNPs) may enhance RNA delivery for glioblastoma treatment by overcoming barriers like blood-brain barrier penetration.

RNA-based therapeutics show promise for targeting glioblastoma but face challenges such as RNA instability and inefficient delivery.
LNPs are noted for their biocompatibility and high RNA encapsulation efficiency, making them effective delivery vehicles.
Recent advances in LNP formulation optimization include modifications to lipid composition and surface ligands.
Delivery routes like intranasal and intra-arterial are being explored to improve LNP-mediated RNA delivery to glioblastoma.
Combining LNP-based gene therapeutics with chemotherapy and immunotherapy could enhance treatment outcomes for glioblastoma.
Artificial intelligence integration in LNP development may lead to personalized RNA therapies for glioblastoma patients.

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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.

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

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