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Life sciences · Journal article
Advanced Science · October 18, 2026
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ABSTRACT Methylselenol (CH 3 SeH) is not only a key selenium (Se) metabolite but also a potent therapeutic molecule. Chemical tools for stimulus‐responsive delivery of CH 3 SeH should be crucial for exploring Se‐related biomedicine. Nevertheless, the classical 1,6‐self‐immolation is inefficient in releasing the poorly leaving selenol, and donation platforms for triggerable release of the CH 3 SeH remain lacking. Herein, we report the first general responsive platform (Triggered Donation for MethylSelenol, termed TD‐MSe) via fast intramolecular amino‐activated methylselenocarbamates ( t 1/2 = 5 s at pH 7.4), enabling the efficient cyclization release of CH 3 SeH without electrophilic byproducts. We leverage the caged TD‐MSe motifs to successfully create triggered donors that are stable before activation but can liberate CH 3 SeH under different stimulus conditions in vitro and in live cells. Additionally, we demonstrate that the tumor‐associated oxidoreductase (hNQO1)‐triggered CH 3 SeH donor was activated in hNQO1‐positive HT‐29 cells but not in hNQO1‐negative cells. Moreover, we can use the CH 3 SeH prodrug to selectively kill metastatic cells of hNQO1‐overexpressing cancer types, providing a promising therapeutic strategy for difficult‐to‐treat diseases. We anticipate that the new‐release chemistry will be widely applied for developing advanced tools toward smart selenol delivery and therapy.