Design and Engineering of Metal Catalysts for Bio-orthogonal Catalysis in Living Systems

In the past two decades, bio-orthogonal transformations mediated by biocompatible metal catalysts in living systems have shown enormous potential in both synthetic biology and medicinal chemistry. These metal-mediated bio-orthogonal reactions, many of which could not be accomplished by natural enzymes, have created more possibilities in organic chemistry and biological sciences. Despite all of the challenges for making those abiotic catalysts work in complicated biological environments, many catalytic systems working in living systems have been reported, mediating different transformations such as uncaging of fluorescent probes, pro-drug activation, glycan or protein activation, labeling of proteins or cell surfaces, and in situ drug synthesis. This review categorizes and summarizes the recent development of synthetic metal catalysts for bio-orthogonal reactions in living systems within two decades. Ranging from simple metal complexes and macromolecular-scaffold-based catalytic systems to heterogeneous nanomaterial-based systems, we show those catalysts of diverse nature and highlight the strategies for their design and engineering. We analyze and describe the structure-property relationship of those biocompatible metal catalysts and show the importance of structural diversification and optimization for their potential applications. A brief overview of metal-mediated bio-orthogonal reactions for biological applications is also given, and the challenges and opportunities of this field are discussed from a long-term perspective.