Rethinking Click and Bioorthogonal Chemistry for Biomedical Applications

Over the last two decades, click chemistry and bioorthogonal chemistry have revolutionized the field of biomedical engineering. Extensive investigations have been conducted and allowed for unforeseeable developments in many different fields, including imaging, drug delivery, 3D cell culture, and bioprinting. The properties of advanced click and bioorthogonal chemical tools have now exceeded the expectations set by the researchers who first introduced the two concepts, calling for reevaluation. More importantly, their developments in distinct research contexts have led to conceptual divergences, which can now be a source of misunderstandings and disagreements. This perspective article aims to take a fresh look at the two concepts, with particular attention to their combination for applications in biological environments. After a short historical introduction, the definitions of click chemistry and bioorthogonal chemistry are revised, and the concept of ideal click chemistry is introduced. Chemical reactions that are commonly considered as click and bioorthogonal reactions are discussed in light of this new perspective. Finally, current challenges and new chemical concepts are presented, offering a new framework for future research.