Precise bioconjugation

Site-specific bioconjugation means attaching molecules at a defined position on a protein, with controlled stoichiometry. Random conjugation methods produce heterogeneous mixtures that complicate manufacturing, analytics, and regulatory filing. A genetically encoded ncAA with a click-chemistry handle addresses this by providing a single, defined attachment point.

Researchers incorporated azidolysine (AzK) at a chosen site on AAV capsid proteins, then used click chemistry to attach an anti-HER2 nanobody. The resulting targeted AAV vector achieved a 19-fold increase in gene delivery to HER2-positive tumours in vivo, compared to unmodified AAV. The same approach worked with full-length trastuzumab (Pham et al., 2025).

Site-specific ncAA conjugation applies broadly beyond gene therapy: antibody-drug conjugates, PEGylation for half-life extension, fluorescent labelling for diagnostics, and multi-domain protein assembly. The common advantage is homogeneity, where each molecule is modified at the same site in the same way, simplifying manufacturing and improving batch consistency.