Review of intranasal ethosomal nanocarriers for brain delivery that emphasizes ethanol-enhanced membrane fluidity, penetration enhancers, and functionalization to improve nose-to-brain transport, while noting mostly preclinical data and unresolved safety/absorption issues.

Intranasal ethosomes could enable noninvasive, targeted delivery of Parkinson's therapeutics (e.g., neuroprotective agents or biologics) to the brain and reduce systemic exposure, but translation is limited by safety concerns and lack of clinical validation.

Neurological diseases such as Alzheimer's disease, Schizophrenia, anxiety, Parkinson's disease, and migraine are serious conditions that continue to threaten mankind. The cases of brainrelated disorders are increasing worldwide and are closely related to physiological, genetic, and environmental factors. Direct drug delivery to the brain is crucial for the effective treatment and prevention of these conditions. However, due to the presence of a lipophilic barrier, i.e., the bloodbrain barrier, the entry of therapeutic agents into the brain is restricted, resulting in a lower concentration at the targeted site. As a solution to this problem, the direct nose-to-brain connection is attracting attention for its effective, precise, non-invasive delivery of drugs via the olfactory and trigeminal pathways. However, there are some limitations, like permeability across the nasal mucosa and mucociliary clearance. Therefore, to overcome these restrictions, the use of nanocarriers, particularly ethosomes, is being attempted. This review paper delves into recent research papers and reports on ethosomes developed for intranasal delivery towards the management of neurological conditions. Ethosomes demonstrated an exceptional capacity to facilitate drug accumulation at targeted sites, owing to their ability to bypass first-pass metabolism, their flexible nature, and the presence of penetration enhancers. The high ethanol content in the composition significantly increases the fluidity of the lipid bilayer, allowing for better interaction of this vesicular system with the blood-brain barrier. Furthermore, the functionalization of ethosomes can enhance the specific delivery of drugs, increase patient compliance, and minimize side effects. However, no intranasal ethosomes for direct brain delivery have progressed from preclinical testing to the bedside of patients. They are still in the experimental phase, particularly in animals or in vivo lab models. The possibilities of toxic effects, the use of high amounts of ethanol, and irregular nasal absorption are a few concerns that need to be addressed. The increasing demand for intranasal delivery suggests that ethosomes may play a pivotal role in the management and treatment of brain-related conditions, but this will only occur after a substantial number of clinical trials confirm their safety and efficacy for human consumption. This review explores such possibilities and highlights current trends and future perspectives in targeting the brain with ethosomal formulations.