Blood–Brain Barrier: Structure, Function, Diseases, and Drug Delivery Systems

The blood-brain barrier (BBB) is a highly selective and dynamic neurovascular interface essential for maintaining central nervous system homeostasis. This specialized barrier comprises brain microvascular endothelial cells interconnected by tight junctions, supported by pericytes and astrocytic end-feet within the neurovascular unit. While protecting the brain from circulating pathogens and toxins, the BBB presents formidable obstacles to drug delivery, restricting approximately 98% of small-molecule therapeutics and nearly all large biomolecules from reaching the brain parenchyma. BBB dysfunction is critically implicated in the pathogenesis and progression of numerous neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and brain tumors. This comprehensive review systematically examines the structural organization and functional characteristics of the BBB, elucidates its pathophysiological roles across major neurological diseases, and critically evaluates innovative drug delivery strategies designed to overcome this biological barrier. We analyze passive targeting approaches, active targeting mechanisms via receptor-mediated transcytosis, and stimuli-responsive systems including focused ultrasound and magnetic guidance. Additionally, we discuss multifunctional nanoplatforms, biomimetic cell membrane-coated delivery systems, current preclinical evidence, and clinical translation challenges. Finally, we propose future research directions and identify specific experimental pathways to accelerate the development of next-generation BBB-targeted therapeutics from preclinical promise to clinical application.