Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and brain tumors remain major global health burdens due to complex pathology and the restrictive nature of CNS barriers, including the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Non-invasive nose-to-brain delivery has emerged as a promising strategy to bypass these barriers and lipid-based nanostructures such as solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions, liposomes and vesicular systems are gaining prominence for their biocompatibility and ability to encapsulate both hydrophilic and lipophilic therapeutics. This review summarizes the advancements in targeted lyophilised lipid-based nanocarriers for central nervous system (CNS) drug delivery, covering anatomical barriers, nose-to-brain transport mechanisms, formulation strategies and solidification techniques like freeze-drying and spray-drying that improve stability and usability. Key findings indicate that lyophilisation enhances structural integrity, long-term storage and reconstitution without loss of efficacy. Comparative advantages include improved mucoadhesion, protection from enzymatic degradation, sustained and stimuli-responsive release, and better patient compliance, further strengthened by surface modifications that enhance targeting efficiency. The review highlights recent clinical progress and patent developments, emphasizing the translational potential of these systems. It also addresses major challenges, including scale-up barriers, lipid polymorphism, cryoprotectant optimization, aggregation risks, long-term safety concerns and regulatory hurdles. Overall, lyophilised lipid-based nanostructures offer a versatile and promising platform for CNS therapeutics. Future perspectives focus on overcoming existing limitations and developing next-generation hybrid, stimuli-responsive and precision-targeted systems to advance effective neurological drug delivery.
