Enzyme‐Triggered Chemodynamic Therapy via a Peptide‐H ₂ S Donor Conjugate with Complexed Fe ²⁺

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic (CDT). Relying on delivery Fenton reaction promoters such as Fe2+, CDT takes advantage overproduced ROS in the microenvironment. We developed peptide-H2S donor conjugate, complexed with AAN-PTC–Fe2+. The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed glioma cells, to release carbonyl sulfide (COS). Hydrolysis COS carbonic anhydrase formed H2S, inhibitor catalase, that detoxifies H2O2. Fe2+ and H2S together increased intracellular decreased viability C6 compared controls lacking either sequence, or ability generate H2S. AAN-PTC–Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides H2S-amplified, enzyme-responsive platform for synergistic treatment.