10128-ET-1 Development of Dual-Delivery Nanoparticles for Malignant Glioma: Tumor-Targeted and BBB-Penetrating siRNA/mRNA Therapeutics

Abstract Nucleic acid therapeutics, which allow for specific regulation of target genes, represent a promising strategy for cancer treatment. However, their clinical application to brain tumors remains limited, primarily due to the presence of the blood-brain barrier (BBB), a physiological obstacle that hinders drug delivery. In this study, we aimed to establish a novel dual drug delivery system (DDS) that enables both efficient brain penetration and tumor cell-specific targeting by employing a two-pronged approach using mRNA and siRNA. [1] Development of tumor-targeted siRNA-LNPs:We constructed lipid nanoparticles (LNPs) encapsulating VEGF-targeting siRNA, further modified with Fc-binding peptide lipids (FcBP) and anti-PD-L1 antibodies. These modifications significantly enhanced binding and growth-inhibitory effects against murine glioma cells (GL261). In a subcutaneous tumor model, the treatment resulted in a significant reduction in tumor volume and bioluminescence signals, demonstrating the therapeutic potential of this molecularly targeted DDS. [2] Brain delivery strategy using FUS and mRNA-LNPs: Luciferase mRNA-encapsulated LNPs were intravenously administered to normal mice, followed by focused ultrasound (FUS) irradiation in combination with microbubbles (MB), to transiently and selectively open the BBB. As a result, gene expression in the irradiated brain region was approximately 20-fold higher than in the non-irradiated side, and mRNA delivery into brain parenchymal cells was confirmed. This study highlights a hybrid DDS platform that combines physical BBB opening (via FUS) and molecular targeting (via antibody-modified LNPs), and proposes a novel nucleic acid-based therapeutic strategy for malignant gliomas, particularly those with recurrence or resistance to conventional therapies.