A PEGylated nanobody against HBsAg exhibits pleiotropic antiviral efficacy in hepatitis B models

Hepatitis B virus (HBV) remains a global health burden, with current therapies rarely achieving functional cure, highlighting an unmet need for novel strategies. Here, we isolate a high-affinity nanobody, VHH4917, against the viral surface antigen (HBsAg) from an alpaca nanobodies phage library. VHH4917 exhibits a multi-phenotypic antiviral profile that extends beyond mere neutralization. It not only accelerates HBsAg clearance in vivo but also potently suppresses HBV replication, transcription, and particle secretion through distinct mechanisms. Further engineering by site-specific PEGylation markedly prolongs its circulating half-life and enhances in vivo antiviral efficacy in mouse models of chronic HBV infection. Our work characterizes VHH4917 as a potent, novel therapeutic candidate and provides a promising protein-engineering framework for advancing nanobody-based immunotherapy against chronic hepatitis B.