The blood-brain barrier: Physiology and strategies for drug delivery

Abstract The blood-brain barrier (BBB) is a dynamic structure that functions as a gatekeeper, reflecting the unique requirements of the brain. In this review, following a brief historical overview of how the concepts of the BBB and the neurovascular unit (NVU) developed, we describe its physiology and architecture, which pose a particular challenge to therapeutic intervention. We then discuss how the restrictive nature of this barrier can be overcome for the delivery of therapeutic agents. Alterations to drug formulation offer one option, in part by utilizing distinct transport modes; another is invasive or non-invasive strategies to bypass the BBB. An emerging non-invasive technology for targeted drug delivery is focused ultrasound that allows for the safe and reversible disruption of the BBB. We discuss the underlying mechanisms and provide an outlook, emphasizing the need for more research into the NVU and investment in innovative technologies to overcome the BBB for drug delivery.