Engineering silica nanoparticle-based drug delivery systems for glioblastoma therapy

Glioblastoma (GBM) remains the most aggressive primary brain tumor, with poor prognosis despite multimodal treatment consisting of surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy. Therapeutic failure is largely attributed to the presence of the blood–brain barrier (BBB) and blood–tumor barrier (BTB), tumor heterogeneity, infiltrative growth, and intrinsic or acquired drug resistance mechanisms. In recent years, silica nanoparticles (SiNPs), particularly mesoporous silica nanoparticles (MSNs), have emerged as versatile nanoplatforms for GBM diagnosis and therapy due to their large surface area, tunable pore size, high drug-loading capacity, structural stability, and facile surface functionalization. This review comprehensively summarizes current advances in SiNP-based drug delivery systems (DDS) for GBM, including ligand-mediated targeting strategies to enhance BBB transcytosis and tumor selectivity, stimuli-responsive systems enabling pH- or redox-triggered drug release, combination and co-delivery platforms designed to overcome resistance through synergistic mechanisms, and gene-based approaches for pathway-specific modulation. In addition, theranostic silica-based systems integrating imaging and therapeutic functionalities are discussed. Comparative analysis highlights that while these platforms demonstrate promising preclinical efficacy in improving brain accumulation, tumor targeting, and survival outcomes, significant translational challenges remain, including formulation complexity, tumor microenvironment heterogeneity, large-scale reproducibility, and regulatory considerations. Overall, SiNPs-based systems represent a highly adaptable and rationally engineerable strategy to address key biological and pharmacological barriers in GBM therapy, offering important insights for the future development of precision nanomedicine in neuro-oncology.