Nanotechnology Approaches to Overcome Blood–Brain Barrier in CNS Drug Delivery

The blood–brain barrier (BBB) remains one of the most formidable challenges in central nervous system (CNS) drug delivery, restricting the passage of approximately 98% of small-molecule drugs and nearly all large-molecule therapeutics. This review examines emerging nanotechnology-based strategies developed to overcome BBB limitations and enhance CNS drug bioavailability. Various nanocarrier systems — including polymeric nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, carbon nanotubes, and exosomes — have demonstrated significant promise in facilitating drug transport across the BBB through mechanisms such as adsorptive-mediated transcytosis, receptor-mediated transcytosis, and transient barrier disruption. Surface functionalization with targeting ligands, including transferrin, lactoferrin, and apolipoprotein E, has further improved site-specific delivery efficiency. Additionally, stimuli-responsive nanocarriers activated by pH, temperature, or external stimuli such as focused ultrasound and magnetic fields offer dynamic control over drug release kinetics within the CNS. Despite substantial preclinical progress, translational challenges persist, including nanotoxicity, scalability, immunogenicity, and regulatory hurdles. This review critically evaluates current advances, mechanistic pathways, and the future outlook of nanomedicine in CNS therapeutics, underscoring the transformative potential of nanotechnology in treating neurological disorders such as Alzheimer's disease, Parkinson's disease, glioblastoma, and multiple sclerosis.