Intranasal Chitosan Nano-Formulations: A Novel Frontier in Brain Cancer Therapy

Direct nose-to-brain drug delivery is emerging as a promising approach in neuro-oncology because it offers a non-invasive, needle-free route for delivering therapeutics to the brain while partially bypassing the blood–brain barrier (BBB). This approach takes advantage of the natural connections between the nasal cavity and the central nervous system, allowing drugs administered through the nose to reach brain tissues through the olfactory and trigeminal pathways. Despite its potential, successful clinical translation remains challenging because the nasal cavity presents several physiological barriers. Mucus can trap drug molecules, mucociliary clearance can rapidly remove them, and nasal enzymes can degrade them before they reach their target. Advanced nanocarrier systems are therefore being developed to overcome these barriers and improve drug transport through intracellular, paracellular, and transcellular pathways. In this context, specific structural modifications can enhance drug retention, mucus penetration, cellular uptake, and targeting efficiency. Important strategies include the use of mucoadhesive materials such as chitosan to increase residence time in the nasal cavity; hydrophilic coatings such as polyethylene glycol (PEG) to improve movement through mucus; targeting ligands to promote selective cellular uptake; and stimuli-responsive systems that respond to local conditions such as pH, redox state, or glutathione (GSH) levels. These advances are particularly relevant to the treatment of glioblastoma multiforme (GBM), one of the most aggressive and difficult-to-treat brain tumors. GBM is characterized by extensive infiltration into surrounding healthy brain tissue, making it difficult to achieve effective drug concentrations throughout both the main tumor mass and its invasive margins. Intranasally delivered chitosan-based nano-formulations may help address this problem through a series of transport steps. After administration, the nanoparticles can interact with and remain within the nasal mucosa, move across the olfactory epithelium, and pass through the cribriform plate toward the olfactory bulb. From there, they may distribute into deeper regions of the brain and potentially increase drug accumulation within both the GBM core and infiltrative tumor regions. This review presents a structured overview of engineered chitosan nano-formulations for targeted drug delivery in neuro-oncology. It focuses on their physicochemical properties, mechanisms of nose-to-brain transport, drug-loading strategies, tumor-targeting approaches, therapeutic applications, and the major challenges that must be addressed before clinical translation. Overall, these systems offer a promising strategy for improving the precision and effectiveness of drug delivery to brain tumors and may contribute to the development of more targeted treatments for GBM and other neurological malignancies.