Bioorthogonal chemistry involves selective biocompatible reactions between functional groups that are not normally present in biology. It has been used to probe biomolecules in living systems, and has advanced biomedical strategies such as diagnostics and therapeutics. In this review, the challenges and opportunities encountered when translating in vitro bioorthogonal approaches to in vivo settings are presented, with a focus on methods to deliver the bioorthogonal reaction components. These methods include metabolic bioengineering, active targeting, passive targeting, and simultaneously used strategies. The suitability of bioorthogonal ligation reactions and bond cleavage reactions for in vivo applications is critically appraised, and practical considerations such as the optimum scheduling regimen in pretargeting approaches are discussed. Finally, we present our own perspectives for this area and identify what, in our view, are the key challenges that must be overcome to maximise the impact of these approaches.

Bioorthogonal chemistry refers to reactions that can proceed in biological systems without interfering with biological processes. It has enabled the study of biomolecules in their native environment and has facilitated advanced imaging and diagnostic applications. In their Review (DOI: 10.1002/chem.202203942), M. M. A. Mitry, F. Greco and H. M. I. Osborn critically appraise the suitability of bioorthogonal reactions for in vivo applications. Areas of focus are chemical reactions and the targeting mechanisms used to deliver the bioorthogonal reactions’ components.

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A new and selective breast cancer-targeting prodrug system is described based on the Staudinger ligation bioorthogonal reaction.

Bioorthogonal reactions are biocompatible reactions that enable the study of biomolecules in living organisms. In this review, we summarise and critically appraise recent developments in bioorthogonal reactions for in vivo applications. Areas of focus are the chemical reactions, and the targeting mechanisms used to deliver the bioorthogonal reactions’ components. For more details, see the Review by M. M. A. Mitry, F. Greco and H. M. I. Osborn (DOI: 10.1002/chem.202203942).