10065- ET-6 MRNA-ENCAPSULATED LIPID NANOPARTICLES FOR MALIGNANT GLIOMA

Abstract Nucleic acid therapeutics hold promise for cancer treatment but have yet to be effectively applied to malignant glioma due to challenges in stability and delivery. We explored the intracerebral delivery of lipid nanoparticles (LNPs) encapsulating siRNA as a drug delivery carrier. Our goal was to develop an siRNA therapy selectively targeting malignant glioma cells by combining LNPs with Fc-domain-binding peptide lipids (FcBPs), a modification system that allows antibody orientation control. Intracerebral Delivery of mRNA-Encapsulated Lipid Nanoparticles: We aimed to deliver mRNA-encapsulated LNPs to the brain using focused ultrasound (FUS) and microbubbles (MB). Following the administration of microbubbles and mRNA-encapsulated LNPs in normal mice, FUS irradiation was performed on the brain. The introduction of firefly luciferase mRNA resulted in gene expression that was 20 times higher in the FUS-irradiated brain compared to the non-irradiated side. Gene expression was observed in vascular endothelial cells throughout the brain and in parenchymal cells outside the brain blood vessels at the FUS-irradiated site. Development of siRNA Medicines: We prepared FcBP-modified siRNA-LNPs targeting integrin αvβ3, highly expressed in malignant gliomas, using siRNA-Luc2. The modifications with FcBP or anti-integrin αvβ3 antibody did not alter the physicochemical properties or polydispersity index (PDI). In vitro, anti-integrin αvβ3-FcBP-modified siRNA-LNPs inhibited the binding of integrin to U87-MG-Luc2 cells, demonstrating high binding affinity and knockdown effects via αvβ3.Discussion:Our findings suggest that the delivery of mRNA-encapsulated LNPs into the brain is feasible using FUS and MB. Additionally, we successfully developed siRNA-LNPs modified with anti-integrin αvβ3 antibody FcBP. Future work will evaluate the cell binding and antitumor effects of siRNA-VEGF encapsulated in these LNPs, aiming to develop new treatments for malignant glioma by enhancing blood-brain barrier penetration and targeting malignant glioma.