Bioorthogonal Cleavage Chemistry: Harnessing the Bond‐Break Reactions for Biomolecule Manipulations in Living Systems

Comprehensive Summary The advancement of bioorthogonal cleavage reactions (BCRs) has expanded the scope of the bioorthogonal chemistry toolkit, leading to a diverse array of innovative biological applications. These include but are not limited to precise spatial and temporal activation of intracellular probes, prodrugs, proteins, glycans, and nucleic acids. Herein, we summarize recent efforts by our group to develop BCRs for manipulating functional molecules in living species to meet various needs, along with future perspectives in this exciting field. How do you get into this specific field? Could you please share some experiences with our readers? Chemists are good at both forming and breaking bonds. Back in 2013, while the field of bioorthogonal reactions was continuously thriving, most researchers focused on the "ligation" type of bioorthogonal reactions. Alternatively, I started to wonder whether we could develop the "bond‐cleavage" type of bioorthogonal reactions? We reviewed the literature and found that this is indeed a field that is yet to be developed. I immediately encouraged my graduate students to develop such reactions while I began to look for potential applications for such new chemistry. We soon developed a series of bioorthogonal "cleavage" reactions that can be triggered by metals, small molecules, as well as photocatalysis. We then applied these reactions to activate proteins and other biomolecules, allowing the gain‐of‐function study of their properties inside living cells. Small molecule drugs can also be activated by these reactions within tumor bed, which has led to safer and more efficient anti‐cancer drugs. Over the past decade, we have built a bioorthogonal decaging toolbox that is generally applicable to virtually any molecules of interest, and we are persistently working on broadening the spectrum of reaction types and their applications. This has created a new direction in bioorthogonal chemistry with broad utilities in life sciences and medicine. How do you supervise your students? I encourage students to think independently and collaborate widely. I would be delighted if some of their ideas could let me learn something. In addition to experimental training, I also pay great attention to cultivating students' logical thinking, English writing, and presentation skills. For our regular weekly group meetings, two students will give in‐depth presentations on their research projects, while all group members and I will provide constructive discussions and suggestions. What is the most important personality for scientific research? In my opinion, the most important personality traits for scientific research are curiosity, perseverance, and critical thinking. What is your favorite journal(s)? ACS Chemical Biology. Could you please give us some advices on improving Chinese Journal of Chemistry? Consider organizing special issues that focus on emerging areas of chemistry, which can attract high‐quality submissions and increase the journal's impact.