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

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 Cu²⁺, Fe³⁺, 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 H₂S under acidic conditions, inhibiting the activity of catalase and causing a synergistic effect of local acidification and accumulation of H₂O₂. Cu²⁺/Fe³⁺ disrupts redox balance by depleting glutathione while sustaining Cu⁺/Fe²⁺ release via redox cycling. Citric acid chelates Cu⁺/Fe²⁺, 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.