Clicking in harmony: exploring the bio-orthogonal overlap in click chemistry

In the quest to scrutinize and modify biological systems, the global research community has continued to explore bio-orthogonal click reactions, a set of reactions exclusively targeting non-native molecules within biological systems. These methodologies have brought about a paradigm shift, demonstrating the feasibility of artificial chemical reactions occurring on cellular surfaces, in the cell cytosol, or within the body - an accomplishment challenging to achieve with the majority of conventional chemical reactions. This review delves into the principles of bio-orthogonal click chemistry, contrasting metal-catalyzed and metal-free reactions of bio-orthogonal nature. It comprehensively explores mechanistic details and applications, highlighting the versatility and potential of this methodology in diverse scientific contexts, from cell labelling to biosensing and polymer synthesis. Researchers globally continue to advance this powerful tool for precise and selective manipulation of biomolecules in complex biological systems.