Nanobody conjugated with dendrimer nanoparticles effectively neutralizes tick-borne encephalitis virus

Tick-borne encephalitis virus (TBEV) is a neurotropic flavivirus causing severe meningitis, encephalitis, or meningoencephalitis. The blood-brain barrier (BBB) prevents therapeutic agents from reaching the brain; therefore, specific antiviral therapy that can cross the BBB and treat TBEV-induced infection is urgently needed. In this study, nanobodies (NBs) targeting domain III (DIII) of the envelope (E) glycoprotein of TBEV were developed and conjugated to drug delivery nanosystems based on self-assembling dendrimer nanomicelles (DNs) and gold nanoparticles (AuNs) to facilitate BBB passage and viral neutralization. NBs were derived from the variable region of heavy chain-only llama antibodies and panned against DIII using phage display. The most active NBs were conjugated with DNs and AuNs. Remarkably, the dendrimer nanosystem decorated with the nanobody clone TA3 (TA3-DNs) and the peptide Angiopep-2 effectively crossed the BBB model and neutralized TBEV. Therefore, TA3-DNs constitute a promising candidate for treating TBEV, and merit further validation in animal models for future translational studies.