Therapeutic drugs often cannot effectively cross the Blood-Brain Barrier (BBB) because of its protective properties. The use of conventional treatment methods, such as oral and injectable routes, is limited by poor permeability, enzymatic degradation, systemic toxicity, and efflux transporter- mediated clearance. Advanced nanotechnology-based carriers have improved blood-brain barrier penetration; however, issues related to toxicity, scalability, and invasiveness remain. A new approach that is gaining attention is the trans-vermilion route, which delivers drugs through the vermilion border of the mouth. This site offers efficient systemic access due to its rich vascularity, thin epithelium, and reduced keratinization, thereby avoiding first-pass hepatic metabolism and gastric degradation. Bio-flexible films and nanoformulations provide an effective platform that improves mucoadhesion, controlled release, potential brain targeting, and ease of application. Bioflexible films improve the stability, penetration, and sustained delivery of drugs when combined with nanocarriers such as liposomes, solid lipid nanoparticles, or polymeric nanoparticles, thereby demonstrating significant promise for the treatment of neurological and psychiatric disorders. This study examines recent advances in bio-flexible film-based nanoformulations for brain targeting, highlighting their application via the trans-vermilion route. It also addresses existing limitations, evaluation methodologies, therapeutic applications, and future prospects for developing personalized, non-invasive, and patient-compliant brain-targeted therapies.
