Nasal nanotherapeutics for central nervous system disorders: Bridging the translational gap in central nervous system drug delivery.

Neurological disorders such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebrovascular accidents, brain tumors, and functional impairments are becoming an increasingly urgent global health concern, particularly as aging populations expand worldwide. The blood-brain barrier significantly limits current treatment strategies, such as pharmacological therapies (oral or systemic), neurosurgical procedures, and neuromodulation. This highly selective barrier prevents most small-molecule drugs and virtually all biologics from reaching effective concentrations within the central nervous system (CNS), thereby restricting their therapeutic potential. Therefore, traditional drug delivery methods face challenges in effectively delivering therapeutic agents to the CNS. Intranasal delivery circumvents this limitation through direct nose-to-brain transport via olfactory/trigeminal pathways, achieving higher cerebrospinal fluid drug bioavailability compared to intravenous routes. In this review, we present a comprehensive elucidation of the pathophysiology of CNS disorders and the intricate mechanisms governing drug transport from the nasal cavity. Significantly advancing the field, we provide an exhaustive overview of cutting-edge nanocarriers and inhalation devices specifically designed for inhalable formulations, highlighting their unique advantages and limitations. This review combines clinical and engineering insights to evaluate innovative treatment methods through intranasal delivery, while identifying critical research pathways for improving central nervous system therapies.