Bioorthogonal synthesis of metal-based anticancer complexes: applications, challenges and perspectives

Relying on the tunable coordination chemistry, unique physicochemical properties of metallodrugs, and inherent multi-target anticancer bioactivity, metal complexes have emerged as a highly promising class of anticancer drug candidates. However, traditional anticancer metallodrugs generally suffer from poor tumor accumulation and non-specific biodistribution, which often lead to severe systemic toxicity and hinder clinical translation. Bioorthogonal reactions, which feature mild reaction conditions, excellent selectivity, and favorable biocompatibility in physiological environments, are well-suited for diverse research scenarios including ligand synthesis, complex construction, biomolecule conjugation, and in situ synthesis in living systems. They represent an ideal technological approach to overcome the inherent limitations of conventional metallodrugs. This review systematically summarizes the latest advances in the application of bioorthogonal reactions for the synthesis of anticancer metallodrugs both in vitro and in vivo . We focus on two core aspects: (i) ex vivo synthesis of metal complexes based on bioorthogonal chemistry, and (ii) in situ complex synthesis systems based on bioorthogonal reactions and nanoparticle-assisted delivery platforms. This review systematically elucidates the structures and anticancer mechanisms of metallodrugs constructed via various bioorthogonal reactions, comparatively analyzes the advantages and principles of different reaction types, summarizes current challenges, and offers a prospective outlook on future directions. Overall, it aims to systematically outline the current status and potential of bioorthogonal chemistry in anticancer metallodrugs, providing theoretical and practical support for translation from basic research to clinical applications and breaking through treatment bottlenecks.