Smart Surface-Engineered Mesoporous Silica Nanoparticles for Brain Tumor Therapy: Overcoming the Blood–Brain Barrier for Advanced Theranostics

Brain tumors, particularly glioblastoma multiforme (GBM), remain among the most lethal forms of cancer due to their aggressive nature and the formidable challenge posed by the blood-brain barrier (BBB), which restricts the delivery of therapeutic agents. Conventional treatment modalities, including surgery, radiotherapy, and chemotherapy, often fail to achieve effective and targeted therapy without inducing systemic toxicity or damaging healthy brain tissue. In recent years, mesoporous silica nanoparticles (MSNs)have emerged as a versatile platform for targeted brain tumor therapy because of their high surface area, tunable pore structure, biocompatibility, and ease of surface functionalization. This review critically examines advanced surface functionalization strategies, including chemical functionalization (amine, thiol, carboxyl groups), ligand conjugation (antibodies, aptamers, peptides), and polymeric coatings (PEG, chitosan, PLGA) that enhance BBB penetration, facilitate tumor-specific targeting, and enable stimuli-responsive drug release (different types of exogenous and endogenous). We also explore the interactions of these modifications with key signaling pathways (e.g., Wnt/β-catenin, PDGF-B, TGF-β) that regulate BBB integrity and glioma progression. Special emphasis is placed on how surface-engineered MSNs can improve site-specific drug delivery, increase therapeutic accumulation in brain tumor tissue, and minimize off-target toxicity. Despite the considerable promise demonstrated by these techniques in preclinical glioma models, obstacles such as scalable synthesis, regulatory compliance, and long-term biosafety must be addressed to facilitate clinical translation. This review focuses specifically on brain tumor targeting via functionalized MSNs and provides mechanistic insights while highlighting emerging strategies to advance MSNs as next-generation therapeutics for brain tumor treatment.