Dual-modified brain-targeting lipid polymer micelle delivery of anti-miRNA-21 for achieving oral treatment of glioma

Glioma represents a predominant intracranial malignancy, with fewer than 40% of patients surviving beyond five years. MiRNA-21 antisense oligonucleotides (anti-miR-21) hold considerable promise for managing aggressive intracranial gliomas. Yet, challenges such as in vivo degradation, suboptimal brain targeting, and inadequate tumor penetration compromise the therapeutic efficacy of unmodified miRNA-21 inhibitors. To overcome these obstacles, we designed an orally-administered, brain-targeted anti-miRNA-21 lipid polymer micelle system (BTMLPMS), dually modified with Ang-2 and TAT. This modification ensures the stable delivery of anti-miR-21, leveraging the protective capacities of lipid polymer micelles to effectively impede glioma growth in vivo. In vitro studies confirmed that these micelles were efficiently uptaken by glioma cells, resulting in induced apoptosis. Importantly, in an orthotopic glioma xenograft model using nude mice, oral administration of these micelles activated pro-apoptotic proteins p53 and Caspase-3, effectively inducing apoptosis in tumor tissues and curbing tumor progression. Hematoxylin-eosin staining further validated the biocompatibility of the micelles. Collectively, our findings underscore the potential of the anti-miR-21 lipid polymer micelle system as a significant advancement in glioma gene therapy, paving the way for groundbreaking transformations in miRNA clinical applications.