Tetrazine-based bio-protection: reversible masking of cell surface thiols for orthogonal cellular chemistry
- 1Radboud University Nijmegen, Institute for Molecules and Materials Heyendaalseweg 135 6525 AJ Nijmegen The Netherlands
Abstract
Cell-surface thiols are redox-sensitive functional groups that regulate cellular signalling, surface reactivity, and thiol-mediated uptake. However, these thiols are highly susceptible to irreversible oxidation during oxidative surface modification procedures, compromising cell viability and functionalization precision. Here, we report a reversible and biocompatible thiol protection strategy using sulfide tetrazines that covalently mask exofacial thiols on live cells via rapid nucleophilic aromatic substitution. This masking renders the thiols inert to oxidative damage, as demonstrated in both polymeric membranes and viable Jurkat and HeLa cells, where tetrazine-treated surfaces resisted NaIO4− induced thiol oxidation. Importantly, the protection is readily reversed by extracellular treatment with glutathione, thus restoring native thiols via nucleophilic aromatic substitution. Furthermore, we show that tetrazine-based protection preserves thiol-mediated cellular uptake capabilities, enabling precise temporal control over cell-surface thiol reactivity. This bio-protection strategy extends the toolkit of bioorthogonal chemistry to conditional masking of thiols, opening new avenues for dynamic cell-surface engineering, redox biology investigations, and controlled bioconjugation strategies in complex cellular environments.
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BibTeX
@article{sun2026tetrazinebased,
title = {{Tetrazine-based bio-protection: reversible masking of cell surface thiols for orthogonal cellular chemistry}},
author = {Mingchen Sun and Katerina Gavriel and Chenxuan Wan and Jelte Schermer and Kevin Neumann and Daniela A. Wilson},
journal = {Chemical science},
year = {2026},
month = nov,
doi = {10.1039/d6sc04306b},
url = {https://europepmc.org/article/PMC/PMC13730538},
note = {CC BY},
}
RIS
TY - JOUR
TI - Tetrazine-based bio-protection: reversible masking of cell surface thiols for orthogonal cellular chemistry
AU - Mingchen Sun
AU - Katerina Gavriel
AU - Chenxuan Wan
AU - Jelte Schermer
AU - Kevin Neumann
AU - Daniela A. Wilson
PY - 2026
DA - 2026/11/03
JO - Chemical science
DO - 10.1039/d6sc04306b
UR - https://europepmc.org/article/PMC/PMC13730538
AB - Cell-surface thiols are redox-sensitive functional groups that regulate cellular signalling, surface reactivity, and thiol-mediated uptake. However, these thiols are highly susceptible to irreversible oxidation during oxidative surface modification procedures, compromising cell viability and functionalization precision. Here, we report a reversible and biocompatible thiol protection strategy using sulfide tetrazines that covalently mask exofacial thiols on live cells via rapid nucleophilic aromatic substitution. This masking renders the thiols inert to oxidative damage, as demonstrated in both polymeric membranes and viable Jurkat and HeLa cells, where tetrazine-treated surfaces resisted NaIO4− induced thiol oxidation. Importantly, the protection is readily reversed by extracellular treatment with glutathione, thus restoring native thiols via nucleophilic aromatic substitution. Furthermore, we show that tetrazine-based protection preserves thiol-mediated cellular uptake capabilities, enabling precise temporal control over cell-surface thiol reactivity. This bio-protection strategy extends the toolkit of bioorthogonal chemistry to conditional masking of thiols, opening new avenues for dynamic cell-surface engineering, redox biology investigations, and controlled bioconjugation strategies in complex cellular environments.
SN - 2041-6520
SN - 2041-6539
ER -