Breaking barriers: exploring blood-brain barrier crossing mechanisms with nanomedicine for effective glioma treatment.

This review comprehensively highlights recent studies on the potential immunotherapy targets and nanomedicine strategies to enhance glioma treatment by overcoming the blood-brain barrier (BBB). Various nanoparticles, such as liposomes, poly (lactic-co-glycolic acid) (PLGA), and gold nanoparticles (AuNPs), have shown a significant ability to cross the BBB and deliver therapeutic agents to glioma. Surface modification of nanoformulation with transferrin, insulin, and trans-activator of transcription (TAT) peptides has proven enhanced cellular uptake and tumor suppression. Self-targeting carbon dots (CDs) have shown effectiveness even without targeting ligands, indicating their broad potential for crossing the BBB. Polymeric nanocapsules (PNCs) encapsulating Methotrexate significantly reduced tumor volumes in animal models of glioma. Additionally, fucoidan-encapsulated Vismodegib nanoparticles effectively crossed the BBB and exhibited minimal toxicity in healthy brain tissue. Synthetic protein nanoparticles (SPNPs) loaded with small interfering RNA (siRNA) achieved an 87.5% long-term survival rate in glioma-bearing mice. Novel systems, such as lipid-calcium phosphate (LCP) nanoparticles and poly (β-L-malic acid), have been utilized to effectively deliver siRNA and immune checkpoint inhibitors, respectively, across the blood-brain barrier (BBB), thereby downregulating programmed death-ligand 1 (PD-L1) expression and regulatory T cell (Treg) activity. Chimeric Antigen Receptor (CAR) T cell therapies combined with nanoparticle-based drug delivery systems enhanced brain tumor-specific targeting and improved immune cell infiltration. Despite the success in preclinical studies, challenges remain regarding nanoparticle biocompatibility, off-target effects, and regulatory approval. Nevertheless, these findings support the potential of multifunctional nanomedicines for glioma therapy by enabling BBB penetration, immune modulation, and targeted drug delivery, which can be further improved.