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

Abstract

Abstract Carbon monoxide (CO) and hydrogen sulfide (H 2 S) 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/H 2 S 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 H 2 O 2 . Leveraging the proximity effect between these modules, exceptional CO release efficiency exceeding 90% was achieved. Surprisingly, H 2 O 2 ‐induced chemiexcitation also facilitated H 2 S release from the 3‐hydroxythioflavone scaffold. Two representative prodrugs demonstrated simultaneous CO and H 2 S 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/H 2 S dual prodrugs, providing a promising strategy for combinatorial gas therapy in cancer treatment.