DSPE-Based Ligand-Cross-Linked Lipid Nanoparticles for BBB/BBTB Transport and Glioma Targeting

Abstract

Insufficient drug accumulation at intracranial tumor sites remains a major obstacle to effective glioma therapy, primarily due to restricted transport across the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB) and limited active targeting to glioma cells. Here, we report DSPE-based ligand-cross-linked lipid nanoparticles (DBLC LNPs) that integrate lipid-interface engineering, ligand cross-linking, and sequential glioma targeting within a single nanoparticle platform. In this design, maltobionic acid (MA)-functionalized DSPE was incorporated to promote glucose transporter 1 (GLUT1)-mediated BBB/BBTB transport, while 3-(propionamido)phenylboronic acid (PAPBA)-functionalized DSPE was introduced to recognize sialic acid-containing glycans on glioma cell surfaces. Compared with many complex multifunctional brain-tumor nanocarriers, this DSPE-based lipid-interface design introduces transport and recognition through defined lipid-ligand conjugates, thereby reducing synthetic complexity while maintaining formulation tunability and cargo-loading flexibility. Microfluidic technology further enabled controlled and reproducible preparation of DBLC LNPs, supporting their formulation compatibility and translational potential. In an orthotopic glioma model, vincristine (VCR)-loaded DBLC LNPs significantly suppressed glioma growth and prolonged survival. Magnetic resonance imaging (MRI)-based 3D reconstruction analysis of brain tumor further showed that DBLC LNPs@VCR inhibited tumor growth more effectively than free VCR, with tumor volume more than 6-fold lower than that in the free VCR group. Together, this study establishes a DSPE-based ligand-cross-linked LNP platform that combines sequential BBB/BBTB transport, drug-loading capacity, and formulation compatibility to improve therapeutic delivery for glioma treatments.