Cubosomal Drug Delivery Systems for Neuroprotection via Nose-to-Brain Delivery: A Detailed Review

Neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and related dementias remain difficult to treat because many therapeutic agents show poor penetration across the blood–brain barrier (BBB) and require long-term administration. Intranasal (IN) administration offers a non-invasive route for direct drug transport from the nasal cavity to the central nervous system (CNS) through olfactory and trigeminal pathways, partially bypassing systemic circulation and the BBB. However, mucociliary clearance, limited dosing volume, enzymatic degradation, and poor solubility of many neuroprotective molecules reduce delivery efficiency. Cubosomes—nanostructured particles derived from bicontinuous cubic liquid crystalline phases—have emerged as a versatile lipid-based platform capable of encapsulating hydrophilic, lipophilic, and amphiphilic payloads, enabling sustained release and improved mucosal permeation. This review summarizes the fundamentals of cubosome structure and composition (monoolein or phytantriol with stabilizers such as poloxamer 407), preparation approaches (top-down, bottom-up), critical quality attributes, and performance considerations for intranasal nose-to-brain delivery. Evidence from preclinical studies of cubosomal intranasal systems—often incorporated into in situ mucoadhesive gels—demonstrates improved brain targeting, enhanced pharmacodynamic outcomes, and acceptable nasal safety for multiple CNS-active drugs. Key design considerations, evaluation models, translational challenges, and future directions (surface functionalization, scalable manufacturing, regulatory quality-by-design) are discussed to guide development of clinically relevant cubosomal nose-to-brain neuroprotective therapies.