Self‐Amplifying Redox Cycle Triggers Ferroptosis/Cuproptosis Synergy for Enhanced Bacterial Eradication

ABSTRACT Ferroptosis and cuproptosis, two emerging forms of metal‐dependent cell death, show potential in combating multidrug‐resistant bacterial infections. However, their effectiveness is constrained by insufficient intracellular iron/copper levels, unintended toxicity to healthy cells. Here, we developed a self‐amplifying, targeted nanocomposite (ct@HMCF‐Dex) based on hollow mesoporous copper‐iron sulfide (HMCF), citric acid (ct), and dextran (Dex), which specifically triggers extracellular bacterial cuproptosis/ferroptosis, effectively treating MRSA lung infections and wound infections. Under the bacterial‐infected microenvironment, ct@HMCF‐Dex can release Cu 2+ , Fe 3+ , S 2− and citric acid in response to the acidic environment, thereby triggering a series of amplified oxidative stress reactions. During this process, S 2− generates H 2 S under acidic conditions, inhibiting the activity of catalase and causing a synergistic effect of local acidification and accumulation of H 2 O 2 . Cu 2+ /Fe 3+ disrupts redox balance by depleting glutathione while sustaining Cu + /Fe 2+ release via redox cycling. Citric acid chelates Cu + /Fe 2+ , prolonging their activity for lipid peroxidation, and activates the tricarboxylic acid (TCA) cycle, synergizing with cysteine depletion to induce cuproptosis/ferroptosis‐like death. This process generates stable hydroxyl radicals (•OH) and effectively clearing free bacteria and disrupting biofilms through a synergistic mechanism. This study presents a precise strategy to combat stubborn infections by triggering targeted bacterial cuproptosis/ferroptosis‐like death.