Light-Driven Bioconjugation of Organometallic Compounds via Aryl Azide Photochemistry

Antibody–drug conjugates (ADCs) represent a clinically established modality for targeted cancer therapy. Many bioconjugation strategies have been developed to create ADCs, utilizing biocompatible chemical reactions for specific antibody modification, maintaining their biological functions. A systematic gap persists in the availability of bioconjugation reactions specifically tailored to enable the covalent attachment of organometallic payloads, thereby constraining the translation of this class of promising drug candidates into the ADC drug-delivery paradigm. Here, we report a general photochemical platform for the generation of photoactivatable organometallic bioconjugates, enabling the mild and straightforward covalent attachment of N-heterocyclic carbene (NHC)–stabilised complexes of various metals (Ru, Cu, Au and Pd) to proteins and monoclonal antibodies (mAbs). By harnessing aryl azide photochemistry, we achieved chemospecific lysine side chain modifications in aqueous conditions while preserving antibody bioactivity. Preliminary tests with human serum albumin (HSA) gave tunable drug-to-protein ratios (DPR), high photoconjugation yields and extended stability under physiologically relevant conditions. Applying these methods to trastuzumab produced antibody–organometallic conjugates with controlled metal loading, minimal aggregation, and preserved antigen-binding activity. In vitro biological evaluations revealed that protein conjugation can enhance the cytotoxicity of the parent complexes, with low micromolar IC50 values for gastric and ovarian cancer cell lines.