Catalytic ROS‐Amplifying Self‐Immolative Linkers Enable Carrier‐Free Prodrugs for Refractory Tumors

Redox-buffering systems in tumors heighten chemoresistance, yet most ROS-responsive linkers used in prodrug design consume oxidants, exhibit limited sensitivity to endogenous ROS, and often require external triggers or complex formulations, constraining clinical translation. Here we report a phenylselanyl cyclohexenone self-immolative linker that couples ROS-triggered cleavage with organoselenium-mediated redox amplification within a single small-molecule architecture. Oxidation of the selanyl group generates a selenoxide that undergoes aromatization-assisted β-elimination followed by 1,6-self-elimination, releasing the payload together with a redox-active selenium species. The released selenium species is proposed to engage in a GSH-dependent redox cycle that increases intracellular oxidative burden, thereby reinforcing ROS-triggered activation and weakening antioxidant buffering. This modular motif enables the construction of carrier-free prodrugs spanning chemotherapeutics and small-molecule inhibitors. These prodrugs remain stable in neutral media yet are efficiently activated by endogenous ROS, achieving improved biodistribution, reduced systemic toxicity, and enhanced antitumor activity across breast cancer, pancreatic ductal adenocarcinoma, and patient-derived leukemia models. By coupling selective activation with catalytic redox amplification, this ROS-amplifying self-immolative linker provides a modular strategy for overcoming redox-associated drug resistance and for advancing the translational potential of small-molecule prodrugs.