Modulation of Bacterial Iron Homeostasis to Enhance Cuproptosis-like Death for the Treatment of Infected Diabetic Wound
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 <i>Staphylococcus aureus</i> (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.
Authors
- Fang Ge (ORCID: https://orcid.org/0000-0002-1605-3225)
- Yujie Tao (ORCID: https://orcid.org/0000-0003-4112-1856)
- Kefeng Pu (ORCID: https://orcid.org/0000-0002-4471-4844)
- Rui Ye
- Xiaomei Shen (ORCID: https://orcid.org/0000-0002-7851-9959)
- Cuicui Ge (ORCID: https://orcid.org/0000-0002-0548-2470)
- Qingrong Dong (ORCID: https://orcid.org/0000-0002-7113-7907)
- Xingfa Gao (ORCID: https://orcid.org/0000-0002-1636-6336)
- Yu‐Chen Chang (ORCID: https://orcid.org/0000-0001-5558-5454)
- Ruhong Zhou (ORCID: https://orcid.org/0000-0001-8624-5591)
Institutions
- The University of Sydney (AU)
- Biotechnology Institute (US)
- University of Groningen (NL)
- Shanxi Medical University (CN)
- Chinese Academy of Sciences (CN)
- Centenary Institute (AU)
- Suzhou Institute of Nano-tech and Nano-bionics (CN)
- Quantitative BioSciences (US)
- Centre de Nanosciences et de Nanotechnologies (FR)
- National Center for Nanoscience and Technology (CN)
- Jiangxi Normal University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- ACS Nano
- Published
- 2025-04-19
- DOI
- https://doi.org/10.1021/acsnano.4c17071
- Citations
- 13
- Primary Topic
- Wound Healing and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 13.34
Funders
- National Natural Science Foundation of China
- Government of Jiangsu Province
- Natural Science Foundation of Jiangxi Province
- Zhejiang University
- Postdoctoral Science Foundation of Jiangsu Province
- National Key Research and Development Program of China