The Blood-Brain Barrier: Anatomical Organisation, Transport Physiology, and Strategies to Overcome It for CNS Drug Delivery: A Focused Narrative Review

The blood-brain barrier (BBB) is a selective interface between the circulation and the central nervous system (CNS) that protects the brain but also limits the entry of most therapeutic agents, large biologics in particular. This focused narrative review summarises the organisation of the BBB as part of the neurovascular unit and describes the physiological routes of transport across it: passive diffusion, carrier-mediated transport, receptor-mediated transcytosis and active efflux by ABC transporters. It introduces the pharmacokinetic parameters and physicochemical properties that govern brain exposure of small molecules, outlines how the barrier changes with ageing and neurodegenerative disease, and compares four groups of delivery strategies: chemical and efflux-directed approaches, nanocarriers, receptor-mediated "Trojan horse" systems, and physical or alternative-route methods such as focused ultrasound and intranasal delivery. Recent review articles were complemented by landmark preclinical and early clinical studies, including a transferrin-receptor antibody shuttle, a transferrin-receptor-targeted enzyme approved in Japan, and focused-ultrasound studies in Alzheimer's disease. The evidence indicates that receptor-mediated transport and focused ultrasound have reached human testing, whereas nanocarriers still need preclinical validation; that no strategy is free of limitations; that standardised preclinical models and head-to-head comparisons are lacking; and that combination approaches guided by imaging and computational modelling are the most promising direction. The review also proposes a cargo-based framework for matching a delivery strategy to the molecule to be delivered. Because it rests on a deliberately limited set of sources, it is intended as a focused synthesis rather than an exhaustive survey. Understanding BBB physiology is the starting point for the rational design of CNS therapeutics.