Reactive oxygen species (ROS) are both byproducts of cellular metabolism and essential signaling molecules, but they need to be carefully regulated as high ROS levels can cause oxidative damage to biomolecules. Bioorthogonal probes activated by ROS would be useful for the design of therapeutics targeting high-ROS-producing cells, such as cancer cells. Now, Ming, Zhang, Mu et al. implement ROS-activated bioorthogonal tetrazine chemistry for therapeutic applications. They designed a boronate-caged tetrazine precursor (BTz) that is uncaged in response to high levels of ROS and oxidized to the desired tetrazine for ligation to trans-cyclooctene (TCO) compounds. They applied BTz to the design of ROS-activated PROTACs and ROS-mediated prodrug release. They used an in situ synthesis strategy for the PROTAC design by using a BTz-tagged E3 ligase ligand and a TCO-tagged molecule, JQ1, targeting BRD4. Treatment of cells with 100 μM H2O2 induced formation of the PROTAC and recruitment of CRBN to BRD4, leading to BRD4 degradation. For the delivery of prodrugs, they implemented a click-to-release strategy using BTz and TCO-modified doxorubicin (Dox) to release Dox in cancer cells, as well as a release strategy using BTz-caged Dox, under 100 μM H2O2. They demonstrated that the click-to-release strategy worked in vivo in tumor-bearing mice to reduce tumor growth. Overall, the development of bioorthogonal probes activated by high ROS levels in tumor cells may be a useful therapeutic strategy. Additional work is needed to test if these probes can be activated with endogenous ROS to understand the basis of ROS homeostasis.
Original reference: Nat. Commun. https://doi.org/10.1038/s41467-026-68771-z (2026)
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