Bacterial cuproptosis-like death: A novel antibacterial strategy based on copper nanomaterials

As the crisis of antimicrobial resistance continues to escalate, there is a growing need for therapeutic approaches that move beyond traditional antibiotic-based paradigms. Bacterial cuproptosis-like death (BCLD) has emerged as a promising concept that leverages intracellular copper overload to trigger cell death. This review elucidates the mechanism of BCLD, which is characterized by a metabolic catastrophe proposed to involve the disruption of lipoylated tricarboxylic acid cycle enzymes and the disintegration of iron-sulfur clusters, ultimately leading to irreversible metabolic collapse and bacterial cell death. The review also details the rational design of copper-based nanomaterials that exploit this vulnerability. A progressive design philosophy is outlined, ranging from basic nanocarriers to systems enabling spatiotemporally controlled delivery, and further to strategies that potentiate BCLD through metabolic sensitization or multimodal synergy. The applications of these engineered platforms are evaluated in challenging infection models, including chronic wounds and implant-associated biofilms, highlighting their combined antibacterial, anti-inflammatory, and tissue-regenerative potential. Finally, we critically discuss key translational challenges, such as the lack of standardized metrics for BCLD quantification, incomplete mechanistic understanding of the core pathway, long-term biosafety concerns, and the bottleneck in scalable material manufacturing. Interdisciplinary research directions are proposed to advance BCLD toward a clinically viable antibacterial strategy.