Bri2 BRICHOS, a molecular chaperone-like domain that can cross brain vascular endothelial cells and deliver proteins into neurons.

The transport of biological drugs from the bloodstream into the central nervous system is hindered by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier, creating a need for efficient and safe delivery systems to the brain parenchyma. Recombinant human (rh) BRICHOS, a chaperone-like domain from the protein Bri2, can access the brain after systemic injection and has shown therapeutic efficiency in Alzheimer model mice. Here, we show that rh Bri2 BRICHOS and cargo proteins fused to it are efficiently transcytosed over human BBB models made of cerebral microvascular endothelial cells and astrocytes. Moreover, intravenously injected protein fused with Bri2 BRICHOS can access the brain parenchyma of mice and enter neurons and astrocytes. Our results suggest that rh Bri2 BRICHOS can be harnessed to deliver cargo from the bloodstream into neurons.