Computationally guided discovery of Ly6e/LY6E-dependent AAV capsid variants

Systemic adeno-associated virus (AAV) delivery to the central nervous system (CNS) would broaden neuroscience studies and therapeutic development, but capsids evolved in mice often underperform across species. We used structure-guided computational prioritization of short peptide inserts predicted to engage the BBB-associated Ly6-family receptor Ly6e/LY6E, grafting candidates into a surface loop of an AAV9 capsid. Selected variants increased blood-brain barrier transduction and enabled widespread CNS gene delivery in Syrian hamsters after intravenous dosing, with lead capsids showing Ly6e-dependent binding and transduction in cell assays. Using the same strategy for the human ortholog, we identified multiple AAV9 variants with LY6E-dependent enhancement of in vitro transduction. These capsids support species-matched CNS delivery and demonstrate how receptor-informed computation can focus experimental screening when in vivo library selection is impractical.