Pharmacological modulation of the blood-brain barrier: Mechanisms, therapeutic strategies, and emerging technologies

The blood-brain barrier (BBB) is a specialized vascular interface that safeguards central nervous system homeostasis by tightly regulating molecular exchange between blood and the brain. While essential for neuroprotection, its restrictive permeability limits therapeutic access, and its dysfunction is increasingly recognized as a driver of pathology across neurodegenerative, inflammatory, cerebrovascular, traumatic, and rare genetic disorders. In this review, we provide a comprehensive overview of pharmacological strategies to modulate BBB function, linking mechanistic insights into tight junction dynamics, transporter networks, endothelial-pericyte interactions, and immune crosstalk to emerging therapeutic approaches. We discuss interventions ranging from small molecules, peptides, and biologics to nanocarriers, noninvasive technologies, gene therapy, and stem cell-based strategies, highlighting their applications in 2 key translational contexts: transient enhancement of drug delivery and restoration of barrier integrity in disease. Ongoing challenges include ensuring safety, accounting for patient heterogeneity, and addressing the limitations of current experimental models. Finally, we consider how advances in BBB-on-chip systems, patient-specific induced pluripotent stem cell-derived models, and novel molecular targets are accelerating translation. Collectively, pharmacological modulation of the BBB, whether by reversible opening to enhance delivery or by reinforcing its protective function, represents a transformative frontier in central nervous system therapy. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a vital safeguard of neural homeostasis and a central obstacle to drug development in the central nervous system. This review integrates mechanistic insights into BBB regulation with translational advances in pharmacology and biotechnology, highlighting strategies that restore barrier integrity in disease and enhance therapeutic delivery. Emerging approaches, including gene therapy, nanotechnology, stem cell-based interventions, and next-generation human-relevant BBB models, illustrate how pharmacological innovation can overcome longstanding challenges and expand therapeutic access to the brain.