Self-Assembled systems for Nose-to-Brain delivery of Temozolamide (TMZ) in brain tumor therapy

Glioblastoma multiforme (GBM) is an aggressive and highly invasive primary brain tumor with poor prognosis and resistance to conventional therapies. The therapeutic efficacy of existing treatments is significantly hampered by the presence of the blood-brain barrier (BBB), tumor heterogeneity, and intrinsic drug resistance mechanisms. Temozolomide (TMZ), the standard chemotherapeutic agent for GBM, suffers from low bioavailability, rapid systemic clearance, and enzymatic degradation, limiting its clinical success. This review highlights the potential of self-assembled nanocarrier-based drug delivery systems for enhancing the therapeutic index of TMZ through intranasal administration, which provides a direct and non-invasive route to the brain, circumventing the BBB and improving central nervous system (CNS) drug bioavailability. Self-assembled systems are highly customizable, allowing for precise control over particle size, surface charge, and release profiles, which can be tailored to improve the penetration and retention of TMZ in the brain. We comprehensively discuss recent advancements in polymeric nanoparticles, liposomes, micelles, niosomes, and solid lipid nanoparticles, emphasizing their physicochemical properties, pharmacokinetics, and mechanisms of targeted drug release. Additionally, we explore molecular and oxidative stress-related pathways contributing to GBM progression and TMZ resistance. Emerging research suggests that nanocarrier-based intranasal delivery of TMZ enhances drug stability, prolongs brain retention time, and minimizes systemic toxicity, offering a promising avenue for improving GBM treatment outcomes.