Modulation of Bacterial Iron Homeostasis to Enhance Cuproptosis-like Death for the Treatment of Infected Diabetic Wound

Abstract

Cuproptosis, an emerging cell death pathway, offers an alternative approach for antimicrobial therapy, but it suffers from deficiencies and health risks. Here, we design hollow Cu-enriched Prussian blue-based nanostructures (Cu-HMPBs) and find that the infected microenvironment facilitates the release of Cu ions from Cu-HMPBs, leading to Cu overload in bacterial cells. Meanwhile, Fe ions in bacterial cells are highly selectively chelated, triggering iron starvation. As a result, the proteotoxic stress and redox imbalance induced by Cu overload are aggravated upon iron starvation, thus remarkably enhancing cuproptosis-like bacterial cell death at extremely low-dose (noncytotoxic) Cu ions. Moreover, we demonstrate the effectiveness of this iron starvation-augmented antimicrobial strategy, and its efficacy is further validated in a methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic mouse wound model. Collectively, these findings provide a promising and universal strategy on iron starvation sensitizing cuproptosis-like bacterial cell death for combating drug resistance.