Harnessing Methylselenol (CH₃SeH): A Highly Effective Platform for Stimuli-Responsive Delivery With Therapeutic...

Methylselenol (CH₃SeH) is not only a key selenium (Se) metabolite but also a potent therapeutic molecule. Chemical tools for stimulus-responsive delivery of CH₃SeH 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 CH₃SeH 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 CH₃SeH without electrophilic byproducts. We leverage the caged TD-MSe motifs to successfully create triggered donors that are stable before activation but can liberate CH₃SeH under different stimulus conditions in vitro and in live cells. Additionally, we demonstrate that the tumor-associated oxidoreductase (hNQO1)-triggered CH₃SeH donor was activated in hNQO1-positive HT-29 cells but not in hNQO1-negative cells. Moreover, we can use the CH₃SeH 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.