Abstract: The blood–brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation. It tightly modulates the ion transport and nutrient influx, while restricting the entry of harmful factors, and selectively limiting the migration of immune cells, thereby maintaining brain homeostasis. Despite the well-established association between blood–brain barrier disruption and most neurodegenerative/neuroinflammatory diseases, much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown. Moreover, the role of blood–brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood. This review aims to revisit this concept of “blood–brain barrier breakdown,” delving into the most controversial aspects, prevalent challenges, and knowledge gaps concerning the lack of blood–brain barrier integrity. By moving beyond the oversimplistic dichotomy of an “open”/“bad” or a “closed”/“good” barrier, our objective is to provide a more comprehensive insight into blood–brain barrier dynamics, to identify novel targets and/or therapeutic approaches aimed at mitigating blood–brain barrier dysfunction. Furthermore, in this review, we advocate for considering the diverse time- and location-dependent alterations in the blood–brain barrier, which go beyond tight-junction disruption or brain endothelial cell breakdown, illustrated through the dynamics of ischemic stroke as a case study. Through this exploration, we seek to underscore the complexity of blood–brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.

Key words: blood–brain barrier disruption, drug delivery, ischemic stroke, neuroinflammation, tight-junctions