Intranasal Therapeutics for Neurodegenerative Disorders: Overcoming the Blood–Brain Barrier with Smart Formulations and Devices

Neurodegenerative diseases have always posed a significant therapeutic challenge due to the restrictive nature of the blood-brain barrier (BBB). Intranasal drug delivery has emerged as a noninvasive approach to bypass the BBB, enabling targeted brain drug delivery while improving drug retention and transport. This review explores the physiological basis of the nose-to-brain pathway and various formulation strategies including mucoadhesive systems, permeation enhancers, and magnetophoretic approaches. Additionally, strategies to enhance intranasal delivery, such as P-glycoprotein inhibitors, cell-penetrating peptides, and enzyme inhibitors, are discussed alongside nanotechnology-based carriers, including surface-modified and bioconjugated systems. The role of specialized intranasal drug delivery devices (e.g., ViaNase, Optimist, and SipNose) in enhancing precision dosing is also highlighted. Despite its promise, intranasal delivery faces challenges such as limited therapeutic windows, scalability issues, and the constraint of the nasal cavity volume, which can accommodate only 200 μL of liquid per nostril. Optimizing drug stability, achieving accurate dosing, and enhancing bioavailability without nasal irritation remain key hurdles. Future research should focus on the development of commercially feasible nanoformulations and innovative medical devices to improve drug targeting and treatment efficacy for patients with neurodegenerative diseases.