Nanoparticle-Based delivery of proteasome inhibitors for glioblastoma Therapy: Strategies to overcome Blood-Brain barrier and therapeutic resistance.

Glioblastoma (GBM), the most malignant primary brain tumor, has a poor prognosis despite surgical resection, radiation, and temozolomide-based chemotherapy. GBM's strong infiltrativeness, intratumoral heterogeneity, activation of compensatory survival mechanisms, and the tight blood-brain barrier (BBB) prevent medication delivery to tumor regions, causing therapeutic failure. Dysregulation of the ubiquitin-proteasome system (UPS), which regulates proteostasis, apoptosis, cell cycle progression, and stress responses, contributes to glioblastoma progression and therapeutic resistance. Thus, proteasome inhibitors (PIs) such bortezomib (BTZ), carfilzomib, ixazomib, and marizomib are promising treatments. However, low BBB penetration, systemic toxicity, and drug resistance mechanisms have hampered its GBM clinical usefulness. Nanoparticle-based therapeutic delivery technologies improve drug solubility, pharmacokinetics, and brain tumor targeting to address these issues. Liposomes, polymeric nanoparticles, dendrimers, inorganic nanoparticles, and exosome-derived vesicles can improve PI bioavailability and treatment efficacy in preclinical GBM models. Surface functionalization with targeted ligands, peptides, and antibodies improves BBB transport and tumor uptake. Stimuli-responsive nanocarriers and multi-modal nanoparticle systems allow regulated drug release and combinatorial delivery of chemotherapeutics, genetic materials, and radiosensitizers. To improve glioblastoma clinical outcomes with nanomedicine and proteasome inhibition, we also explore translational difficulties and prospects. This review provides the UPS's biological role in GBM, proteasome inhibitors and their limitations, and nanoparticle-enabled delivery techniques to bypass BBB barriers and treatment resistance.