Development of albumin and dendrimer-based nanosystems against tick-borne encephalitis virus

Tick-borne encephalitis is a clinically significant arboviral illness with potentially aggressive neurological sequels. Despite available and effective vaccination, the number of human TBE cases has increased over the last three decades. In up to 30% of symptomatic cases, TBEV infection can progress to chronic and persistent encephalitis. Unfortunately, no anti-TBEV therapy is available for chronic patients with a debilitating form of the disease. One of the most promising targets for the development of therapeutics against TBEV is domain III of the viral envelope protein E. Domain III is exclusively exposed on the virion surface and involved in viral attachment and cell entry. Camelid nanobodies (Nb) and small blocking peptides (bP) targeting the DIII offer elegant virus -entry blocking tools thanks to their size and low production costs. Nb and bP, however, do not cross the blood-brain barrier (BBB), a highly selective barrier that prevents common therapeutics from crossing from blood to the brain. The crossing could be improved by their conjugation with biocompatible nanocarriers and BBB-homing peptide (e.g., angiopep- 2). As a proof-of-concept, the project intends to create nanosystems based on PAMAM dendrimer and human serum albumin, which will be decorated with TBEV-blocking Nb or bP and homing peptide. The project also intends to evaluate the stability, safety, and biodistribution of nanosystems in vitro and in vivo. Due to the lack of reporter TBEVs in vivo, we aim to establish a reporter TBEV system to facilitate evaluation in vivo ability of the nanosystems to cross the BBB and neutralize the virus in CNS. We believe that the nanosystems developed and thoroughly evaluated in this project could be translated into anti-TBEV therapeutics.