Advances in light-independent copper-based nanomaterials for antibacterial applications

Antimicrobial resistance (AMR) poses a major global health challenge, while conventional antibiotics are increasingly limited by resistance development and poor efficacy against biofilm-associated infections. Copper-based nanomaterials provide versatile antibacterial platforms through catalytic reactive oxygen species generation, regulated copper-ion release, and copper-overload-induced metabolic disruption. Given the limitations of external light irradiation in deep or light-sensitive tissues, this review focuses on light-independent antibacterial strategies based on copper-containing nanomaterials. Structure-activity relationships of copper single atoms and nanoclusters, copper oxides and sulfides, and copper-based composites are summarized, with emphasis on coordination environment, Cu(I)/Cu(II) redox cycling, defects, interfaces, and ion-release behavior. Two major light-independent mechanisms are discussed: nanozyme catalysis, which promotes oxidative stress and antioxidant depletion, and cuproptosis-like death associated with intracellular copper overload, Fe-S cluster damage, proteotoxic stress, and metabolic dysfunction. Particular attention is given to their reciprocal catalytic-metabolic coupling. Representative in vivo applications, targeting and responsive-delivery strategies, together with biosafety, metabolism, clearance, and translational challenges, are further discussed to guide the rational design of safer and more effective copper-based antibacterial nanomaterials.