CO/H ₂ S Dual Prodrugs Activated by Proximity‐Enhanced Chemiexcitation for Suppression of Tumor Growth and Metastasis

Carbon monoxide (CO) and hydrogen sulfide (H₂S) both exhibit significant therapeutic potential in antitumor therapy, highlighting the importance of developing dual prodrugs for combinatorial gas therapy. However, such dual prodrug systems remain largely unexplored. This study designed a series of CO/H₂S dual prodrugs based on a proximity-enhanced chemiexcitation mechanism. By directly conjugating a chemiexcitation-triggering module with a photosensitive CO-releasing moiety (3-hydroxythioflavone), we constructed unimolecular prodrugs capable of light-independent CO release specifically in response to H₂O₂. Leveraging the proximity effect between these modules, exceptional CO release efficiency exceeding 90% was achieved. Surprisingly, H₂O₂-induced chemiexcitation also facilitated H₂S release from the 3-hydroxythioflavone scaffold. Two representative prodrugs demonstrated simultaneous CO and H₂S release in 4T1 cancer cells. Notably, in a 4T1 murine tumor model, these prodrugs effectively suppressed tumor growth and lung metastasis without inducing observable adverse effects. This work presents the first report of chemiexcitation-triggered CO/H₂S dual prodrugs, providing a promising strategy for combinatorial gas therapy in cancer treatment.