ArticleNature communications2026
Reactive oxygen species-activated bioorthogonal chemistry in living systems enabled by boronate-caged dihydrotetrazines.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed.
- Supramolecular Degraders: An Emerging Paradigm in Targeted Protein Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Red light-responsive bioorthogonal chemistry enabled on-demand prodrug activation for cancer therapy.Acta pharmaceutica Sinica. B · 2026Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Bioorthogonal chemistry has become a robust toolbox with growing applications in biology and medicine. To meet diverse needs in research, new types of on-demand bioorthogonal reactions capable of responding to biological triggers or exogenous stimuli are highly valuable, to achieve spatial and temporal control over reactions in living systems. Elevated levels of reactive oxygen species have been implicated in aging and multiple diseases, serving as remarkable endogenous triggers for prodrugs, probes and materials, however ROS-activated bioorthogonal ligation remains as a challenge. Here we report a reactive oxygen species activated tetrazine ligation enabled by boronate-caged dihydrotetrazines. Bioorthogonal handle tetrazines can be in situ generated from boronate-caged dihydrotetrazines upon the elevated level of hydrogen peroxide, resulting in spatiotemporal control of subsequent reactions with dienophiles. Using this strategy, a reactive oxygen species triggered construction of proteolysis targeting chimera for targeted degradation of the protein of interest bromodomain-containing protein 4 (BRD4) is successfully established by tagging boronate-caged dihydrotetrazines with a cereblon E3 ligase recruiter. Furthermore, we demonstrate a reactive oxygen species triggered tetrazine ligation enabled tumor-selective drug delivery in both living cells and mice. The present reactive oxygen species responsive delivery of cytotoxin doxorubicin via a click-to-release reaction between boronate-caged dihydrotetrazines and trans-cyclooctene modified doxorubicin shows excellent chemotherapeutic efficacy and safety in suppressing the growth of some tumors, superior to both direct administration of doxorubicin and reactive oxygen species sensitive prodrug of boronate-caged doxorubicin. We expect this reactive oxygen species responsive bioorthogonal reaction will offer compelling opportunities for precision therapy and provide approaches for studying pathogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.