After AAV directed evolution led to discovery of a new blood-brain-barrier (BBB) receptor (carbonic anhydrase IV) which facilitates transcytosis, Ding et al. linked a small molecule binder of CA-IV to antibodies, allowing the antibodies to traverse the BBB. This is a major advance since it represents the first time that a receptor target discovered via AAV directed evolution has been adapted to transport other types of molecules across the BBB.

Existing receptor targets to direct delivery of biologics across the blood−brain barrier are ubiquitously expressed in the central nervous system (CNS) and peripheral tissues. Now, carbonic anhydrase IV (CA-IV) is identified as a brain-enriched receptor, enabling selective and prolonged delivery of large molecules to the CNS through conjugation of a small molecule targeting CA-IV.