Precision Nanomedicine for Glioblastoma: Engineering Nanoparticles to Overcome the Blood–Brain Barrier, Tumour Heterogeneity and Therapeutic Resistance

Glioblastoma GBM) is the most aggressive primary malignant brain tumor, with poor clinical outcomes despite maximal surgical resection, radiotherapy, and temozolomide chemotherapy. The limited effectiveness of current therapies is largely associated with the restrictive blood–brain barrier (BBB) and blood–tumor barrier (BTB), extensive intratumoral heterogeneity, glioma stem cell populations, and multiple mechanisms of therapeutic resistance. Nanomedicine offers a promising strategy to address these interconnected challenges through rationally engineered nanoparticles capable of improving brain delivery and therapeutic specificity. This review discusses current approaches for overcoming the BBB/BTB, including receptor-mediated transcytosis, focused ultrasound, convection-enhanced delivery, and intranasal administration. Major nanocarrier platforms, including liposomes, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, metallic nanoparticles, mesoporous silica nanoparticles, and extracellular vesicles, are examined for their therapeutic and theranostic potential. Particular emphasis is placed on multifunctional systems designed to target molecularly heterogeneous GBM populations and overcome resistance mechanisms involving MGMT-mediated DNA repair, drug efflux, PI3K/AKT signaling, and immunosuppressive tumor microenvironments. Emerging strategies integrating biomarker-guided targeting, co-delivery systems, theranostics, artificial intelligence, machine learning, patient-derived organoids, and humanized BBB models may enable personalized nanomedicine. However, challenges involving biological translation, protein corona formation, manufacturing, regulatory requirements, and clinical accessibility remain. Integrated and patient-specific nanoparticle design may provide a future pathway toward more effective precision treatment of GBM.