Enhanced in Vivo Blood–Brain Barrier Penetration by Circular Tau–Transferrin Receptor Bifunctional Aptamer for Tauopathy Therapy

The lack of blood–brain barrier (BBB) penetrating ability has hindered the delivery of many therapeutic agents for tauopathy treatment. In this study, we report the synthesis of a circular bifunctional aptamer to enhance the in vivo BBB penetration for better tauopathy therapy. The circular aptamer consists of one reported transferrin receptor (TfR) aptamer to facilitate TfR-aptamer recognition-induced transcytosis across BBB endothelial cells, and one Tau protein aptamer that we recently selected to inhibit Tau phosphorylation and other tauopathy-related pathological events in the brain. This novel circular Tau–TfR bifunctional aptamer displays significantly improved plasma stability and brain exposure, as well as the ability to disrupt tauopathy and improve traumatic brain injury (TBI)-induced cognitive/memory deficits in vivo, providing important proof-of-principle evidence that circular Tau–TfR aptamer can be further developed into diagnostic and therapeutic candidates for tauopathies.