Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Significance The blood–brain barrier (BBB) poses a major obstacle for drug delivery to the central nervous system (CNS). This study revealed that genetic or pharmacological targeting of sphingosine 1–phosphate receptor-1 (S1P 1 ) facilitates a small-molecule-selective BBB opening, without major signs of CNS inflammation or injury. This size-selective BBB opening could be attributed to changes in the cytoskeletal association of tight junction proteins. Importantly, BBB opening by pharmacological blockage of S1P 1 was reversible, suggesting that targeting S1P 1 may be a promising strategy for the safe delivery of therapeutic agents into the CNS to treat neurodegenerative and neuroinflammatory diseases and neurological cancers.