Copper and its alloys exhibit broad-spectrum antimicrobial activity through both contact-mediated killing and copper ion release, involving Cu²⁺ and Cu⁺ species (Vincent et al., 2018). While the precise molecular mechanisms of contact killing remain partially understood, it is well established that copper ions accumulate on microbial membranes, dissipate transmembrane potentials, and trigger membrane depolarization. This disruption compromises membrane integrity, resulting in rupture, cytoplasmic leakage, and ultimately cell death (Yu et al., 2024). Notably, SARS-CoV-2 has shown pronounced susceptibility to copper surfaces (Van Doremalen et al., 2021). In addition, Cu²⁺ ions have been reported to inhibit papain-like protease two and degrade viral RNA (Rani et al., 2021).

In aqueous and aerobic environments, copper gradually releases ions that initially bind to thiol groups in glycoproteins on microbial surfaces (Długosz et al., 2025). These ions subsequently interact with membrane phospholipids and proteins, enhancing permeability and triggering localized membrane disruption and cytoplasmic leakage (Ren et al., 2025). Upon internalization, copper ions bind intracellular biomolecules—including proteins and nucleic acids—leading to enzyme inactivation, disruption of electron transport, and interference with essential metabolic pathways (Macomber and Imlay, 2009). Copper can also directly engage with DNA and RNA, inducing strand breaks, structural distortions, mutations, or degradation, thereby hindering microbial proliferation and viral replication. Moreover, copper targets iron–sulfur cluster assembly proteins, such as IscU and IscA. Under anaerobic conditions, intracellular copper accumulation in E. coli disrupts Fe–S cluster biogenesis, ultimately compromising bacterial growth and viability (Tan et al., 2017).

Copper-induced oxidative stress significantly contributes to its antimicrobial efficacy. Through Fenton-like reactions and ionic interactions, copper catalyzes the generation of ROS, including superoxide anions (O₂ ⁻), hydroxyl radicals (•OH), and hydrogen peroxide (H₂O₂) (Warnes et al., 2012; Li W. et al., 2018). These ROS initiate lipid peroxidation, enzyme inactivation, and nucleic acid damage—cascading events that ultimately compromise cellular viability. Remarkably, copper exhibits potent toxicity even under anaerobic conditions, where ROS generation is minimal. This ROS-independent lethality is attributed to mismetallation, wherein copper displaces essential metal cofactors such as Fe²⁺ and Zn²⁺ in metalloproteins, resulting in functional inactivation (Zuily et al., 2022). In anaerobic E. coli, copper exposure leads to protein aggregation, likely mediated by Cu-thiol and Cu-histidine interactions in cysteine- and histidine-rich proteins. Strains deficient in molecular chaperones such as DnaK or trigger factor exhibit heightened copper sensitivity, underscoring the role of chaperone-assisted folding in mitigating proteotoxic stress (Zuily et al., 2022). Fu et al. recently introduced a hypoxia-enhanced copper ion interference strategy employing photodynamically activated copper coordination polymer microneedles. This system creates a localized hypoxic microenvironment, promoting sustained Cu⁺ release while concurrently downregulating multicopper oxidase activity, thereby amplifying bactericidal efficacy (Fu et al., 2025). Despite these advancements, the molecular mechanisms underlying copper-induced lethality remain incompletely understood. Excess intracellular copper disrupts core metabolic processes by binding to fatty acylated intermediates in the tricarboxylic acid (TCA) cycle, destabilizing Fe-S cluster-containing proteins, and inducing metabolic collapse—together culminating in irreversible cellular dysfunction and death (Tsvetkov et al., 2022).

Cuproptosis-like death in bacteria describes a copper-induced cell death mechanism, analogous to eukaryotic cuproptosis, but specific to bacterial cells. In bacteria, Cu⁺/Cu²⁺ ions disrupt TCA cycle enzymes and Fe-S cluster biogenesis, inducing similar metabolic failure but lacking the protein aggregation hallmark of eukaryotic systems (Tan et al., 2017; Hua et al., 2024). This process involves the disruption of the TCA cycle and associated metabolic pathways by copper ions, culminating in oxidative stress and eventual cellular demise (Hua et al., 2024). To potentiate this lethal mechanism, a novel MnO₂-loaded copper metal–organic framework (MCM) was engineered to reprogram bacterial respiration and enhance cuproptosis-like death. In hypoxic biofilms, MCM catalyzes H₂O₂ decomposition and in situ oxygen generation, alleviating biofilm-associated hypoxia and shifting bacterial metabolism from anaerobic glycolysis toward aerobic respiration—thereby increasing TCA cycle activity and susceptibility to copper-induced toxicity (Luo et al., 2024). Copper ions specifically target iron–sulfur cluster proteins (e.g., IscU, IscA) and TCA cycle enzymes, particularly dihydrolipoamide S-acetyltransferase (DLAT), causing intracellular copper accumulation, DLAT aggregation, and triggering a cascade of metabolic collapse (Tan et al., 2017; Tsvetkov et al., 2022). Simultaneously, hypoxia reversal reactivates immune cell function and promotes osteogenesis and angiogenesis, while oxygen-rich environments enhance macrophage activity, supporting bacterial clearance (Luo et al., 2024). This spatiotemporal modulation of the microenvironment presents a promising strategy for biofilm eradication and concurrent tissue regeneration. The efficacy of this approach has been demonstrated across multiple studies: Luo et al. showed S. aureus biofilm eradication in vivo via this mechanism (Luo et al., 2024), while Hua et al. demonstrated similar effects in P. aeruginosa pneumonia models, with aerobic respiration amplifying cuproptosis (Hua et al., 2024). However, while metabolic reprogramming via MnO₂-loaded copper frameworks has proven effective in S. aureus and P. aeruginosa, validation in diverse strains (e.g., Klebsiella pneumoniae, Acinetobacter baumannii) and multispecies biofilms is needed to confirm universality (Kuyukina et al., 2025). Additionally, in vitro models may not fully capture physiological complexity, necessitating further in vivo studies (Luo et al., 2024).

Copper demonstrates potent virucidal activity against a broad spectrum of both enveloped and non-enveloped viruses, including single- and double-stranded RNA and DNA viruses. The effect is particularly pronounced for enveloped viruses such as SARS-CoV-2 and influenza virus (Warnes et al., 2012), but also extends to resilient non-enveloped viruses like norovirus and rotavirus (Albalawi et al., 2024). Copper impairs viral infectivity through multiple mechanisms. By disrupting the lipid bilayer of viral envelopes or capsids, copper causes structural disintegration and subsequent inactivation (Mertens et al., 2022; Manuel et al., 2015). It can also bind to viral surface proteins—such as the spike glycoprotein (S protein) of SARS-CoV-2—altering their conformation and thereby hindering host receptor engagement, ultimately preventing viral entry and replication (Hilton et al., 2024). As a transition metal with oligodynamic properties, copper is capable of displacing essential metal ions in metalloproteins, leading to enzymatic inactivation in viral or microbial systems. Furthermore, copper directly interacts with viral nucleic acids, inducing irreversible degradation. Given their limited capacity for nucleic acid repair, viruses are particularly susceptible to copper-mediated genomic damage (Rakowska et al., 2021). Beyond ionic mechanisms, copper surfaces exert direct antiviral effects: upon physical contact, viral particles undergo rapid structural breakdown independent of ion diffusion, highlighting the critical role of surface-mediated inactivation in the overall antiviral efficacy of copper-based materials (Hilton et al., 2024).

Copper-based nanomaterials, including copper nanoparticles (Cu NPs), Cu₂O, and CuO, offer enhanced antimicrobial efficacy compared to bulk copper due to their high surface-area-to-volume ratio and rapid ion release (Woźniak-Budych et al., 2023). These materials disrupt microbial membranes, induce ROS, and interfere with metabolic processes, with mechanisms varying by nanomaterial type and environmental conditions. Copper nanomaterials exhibit multifaceted antimicrobial action, summarized in Table 1. Membrane disruption occurs via ion-mediated depolarization and physical contact, while ROS generation causes oxidative damage. The “Trojan horse” mechanism involves nanoparticle internalization, releasing copper ions intracellularly to amplify toxicity. Biofilm inhibition is enhanced by ROS and quorum sensing (QS) disruption, though efficacy depends on concentration and exposure duration (Mammari et al., 2022). In addition to their antibacterial effects, copper nanoparticles have demonstrated antiviral potential by directly interacting with viral envelope proteins or host cell receptors, thereby obstructing viral entry and subsequent replication (Bhatti and DeLong, 2023).

Compared to bulk copper, nanocopper exhibits markedly enhanced microbicidal efficacy, largely attributable to its elevated surface-area-to-volume ratio, accelerated ion release kinetics, and efficient Fenton-like redox activity (Zhao et al., 2023). Through redox cycling, nanocopper facilitates the generation of ROS, including hydroxyl radicals, superoxide anions, and hydrogen peroxide. These oxidative intermediates elicit widespread cellular damage by inducing lipid peroxidation, protein denaturation, and nucleic acid fragmentation via both enzymatic and non-enzymatic pathways (Salah et al., 2021; Warnes et al., 2012; Li W. et al., 2018).

Additionally, nanocopper undergoes rapid dissolution, releasing Cu⁺ and Cu²⁺ ions that interact with membrane phospholipids and intracellular targets, thereby amplifying oxidative stress (Wei et al., 2024). Importantly, extracellular ion release alone does not fully account for the observed antimicrobial potency. Rather, the internalization of copper nanoparticles and their subsequent intracellular degradation lead to a localized surge of bioactive copper ions within the cytoplasm. This intracellular ion burst triggers excessive ROS generation, ultimately causing widespread cellular dysfunction and death—a phenomenon commonly described as the “Trojan horse” mechanism of copper (Ma et al., 2022).

Bacterial biofilms, composed of self-secreted extracellular polymeric substances (EPS), provide enhanced protection against environmental stressors and antimicrobial agents. These complex, multicellular structures—often found on moist surfaces—pose a formidable challenge to treatment. As biofilms mature, their resistance to copper-based antimicrobials significantly increases. Among various disruption strategies, the generation of ROS at the nanoparticle interface plays a central role in microbial inactivation and biofilm dispersal (Sedighi et al., 2024). For instance, chloride- and nitrite-enhanced Cu-Fenton chemistry has demonstrated effective biofilm degradation through accelerated ROS production (Wang et al., 2017b; Wang et al., 2021).

Copper nanoparticles further inhibit biofilm formation by disrupting QS, the microbial communication system governing biofilm development (Desai et al., 2021). Copper (II) complexes coordinated with aromatic nitrogen-containing heterocycles have emerged as potent QS inhibitors, particularly in Pseudomonas aeruginosa (Glišić et al., 2016). The expanding application of copper-based nanomaterials in oral hygiene and wound care has garnered attention. Notably, copper-based carbon dots (Cu-CDs) have demonstrated the ability to inhibit Streptococcus mutans adhesion and promote biofilm dispersion, positioning them as next-generation antibiofilm agents for clinical use (Liu et al., 2022).

To further enhance antibiofilm efficacy, copper-based nanotherapeutics inducing cuproptosis-like bacterial death have been developed. Lung-targeting Cu₂O–BSO nanoparticles penetrate mucus barriers and amplify cuproptosis by depleting glutathione via buthionine sulfoximine (BSO), simultaneously disrupting QS, biofilm formation, and bacterial virulence while promoting macrophage-mediated clearance (Hu et al., 2025). In parallel, PEG4000-assisted CuCo₂O₄ nanoflowers exhibit enhanced multienzymatic activities, generating ROS and depleting GSH to disrupt bacterial metabolism. Cu²⁺ overload compromises the TCA cycle and respiration, ultimately triggering cuproptosis-like death. Both platforms demonstrate robust in vivo efficacy against MRSA pneumonia and biofilm-infected wounds, offering a synergistic strategy for combating drug-resistant pathogens (Wang et al., 2024).

Copper-based nanomaterials typically require high concentrations to effectively inhibit biofilm formation (Siddique et al., 2024). However, elevated copper levels raise concerns regarding environmental toxicity (Wang and Wang, 2022). Compounding this issue, emerging evidence suggests that copper may accelerate the dissemination of AMR (Zhang et al., 2019), emphasizing the need to elucidate the mechanisms underlying copper-mediated biofilm disruption and to define a safe yet efficacious therapeutic window. In a pivotal study, Kuyukina et al. systematically examined the dual effects of Cu²⁺ released from copper oxide nanoparticles (CuO NPs) on bacterial biofilms and host cell resilience, providing key insights for the rational design of next-generation anti-biofilm nanomaterials (Kuyukina et al., 2025). At sublethal concentrations, CuO NPs exhibit limited affinity for bacterial cell walls, inducing only minor structural perturbations. Interestingly, the resulting increase in surface roughness enhances cellular adhesion, paradoxically promoting biofilm formation. In Rhodococcus spp., intracellular ROS levels initially rise but later decline, suggesting an adaptive oxidative stress response to prolonged low-dose CuO NP exposure. This is accompanied by moderate accumulation of proteins and polysaccharides in the extracellular matrix, supporting a gradual increase in biofilm biomass. Conversely, at higher concentrations, CuO NPs aggregate extensively on bacterial surfaces, inhibiting adhesion and co-aggregation—the critical early steps of biofilm formation. Some nanoparticles penetrate the cell envelope and accumulate intracellularly, triggering a burst of ROS production. This culminates in membrane rupture, metabolic collapse, and widespread bacterial death in an avalanche-like cascade. The sharp elevation in ROS and concurrent suppression of metabolic activity within Rhodococcus biofilms indicate a failure of most cells to mount a protective oxidative stress response. A minority of surviving cells may activate DNA repair pathways, upregulate antioxidant enzymes, or increase EPS production to mitigate nanoparticle-induced damage. Biofilms formed under high CuO NP stress exhibit significantly increased lipid content (∼27%) and a twofold enrichment of proteins and polysaccharides, likely resulting from matrix debris of lysed cells and reduced viable biomass. Notably, intracellular carotenoid levels are markedly elevated, potentially functioning as antioxidant shields against ROS-mediated cytotoxicity. While CuO NP exposure does not visibly alter cellular morphology within biofilms, it induces plasma membrane damage and cytoplasmic heterogeneity, possibly due to dysregulated ion fluxes (Na⁺, Ca²⁺, Mg²⁺ and K⁺) and perturbed metabolic stress responses (Kuyukina et al., 2025). However, it is important to note that these findings are derived from in vitro models using a single bacterial genus Rhodococcus, and may not fully capture the complexity of multispecies biofilms or host-associated environments. Further studies are needed to validate these mechanisms across broader microbial communities and under physiologically relevant conditions.

A defining characteristic of copper nanoparticles is their exceptionally high specific surface area, a property that underpins their potent antimicrobial activity. This enlarged interfacial domain enables intimate contact with microbial membranes, facilitating a spectrum of direct physicochemical interactions. Notably, localized mechanical rupture, membrane perforation, and pressure-induced deformation collectively undermine the structural integrity of microbial cells. This phenomenon—termed the “nanotextured surface contact-killing effect”—has gained increasing recognition as a pivotal mechanism underlying nanoparticle-driven antimicrobial efficacy (Bhatti and DeLong, 2023). While increasingly recognized, the precise contribution of this contact-mediated disruption under physiological conditions, and its potential cytotoxicity to host tissues, remains incompletely defined and warrants further systematic investigation.

Conventional copper and its alloys, including brass and bronze, have long been recognized for their inherent antimicrobial properties, and are extensively employed in plumbing systems, kitchenware, high-touch surfaces such as door handles, and medical instruments. Notably, several copper alloys have been officially approved by the U.S. Environmental Protection Agency (EPA) for antimicrobial use within healthcare infrastructure (Borkow and Gabbay, 2009; Dauvergne and Mullié, 2021). The fabrication of copper-based materials typically involves traditional methods such as melting and casting, powder metallurgy, and electroplating, although emerging techniques continue to expand the manufacturing landscape (Rodrigues et al., 2021). The antimicrobial efficacy of these materials is modulated by multiple physicochemical factors, including copper content, surface roughness, microstructural architecture, environmental parameters, alloying constituents, and the composition and thickness of the surface oxide layers (Georgakopoulos-Soares et al., 2023; Birkett et al., 2022).

In general, higher copper content, increased surface roughness, refined microstructures, humid or acidic environments, the incorporation of reactive alloying elements, and thinner oxide layers are all positively correlated with enhanced antimicrobial activity (Birkett et al., 2022; Zhang et al., 2021; Ding et al., 2019). The antimicrobial efficacy of copper can be substantially improved through surface engineering strategies such as cold spraying and shot peening. Cold spray treatment induces localized grain refinement and dynamic recrystallization, resulting in high-density grain boundaries and submicron structures that accelerate copper ion release and strengthen antibacterial performance (Sousa et al., 2021; Razavipour et al., 2022). Bulk surface nanocrystallization, a more advanced approach, further increases dislocation density and refines grain size, facilitating faster ion diffusion and yielding superior antimicrobial outcomes (Acharya et al., 2021; Azadmanjiri et al., 2015). To elucidate the relationship between crystallographic orientation and antimicrobial activity, Hirota et al. investigated copper thin films exhibiting distinct crystal orientations. Their study revealed that Cu(100)-oriented films, which mimic single-crystal copper, form a stratified Cu/Cu₂O/CuO architecture from the substrate surface outward. This layered structure accelerates Cu₂O formation and introduces surface defects such as steps, kinks, and facets—structural features that enhance ROS generation and improve antimicrobial efficacy against E. coli, S. aureus, and A/Hong Kong influenza virus (Hirota et al., 2025).

Upon prolonged exposure to ambient air and moisture, copper surfaces undergo sequential oxidation, initially forming a reddish-brown Cu₂O layer followed by a black CuO layer, accompanied by a gradual decline in antimicrobial efficacy. The physicochemical properties of these oxides play a central role in modulating corrosion resistance, redox behavior, and biocidal performance. Cu₂O, which releases monovalent Cu⁺ ions, demonstrates superior redox activity and potent antimicrobial efficacy compared to CuO, rendering it more suitable for rapid-disinfection applications such as medical coatings, functional textiles, and air filtration systems. In contrast, CuO exhibits greater chemical stability but reduced antimicrobial activity, making it preferable for long-term antimicrobial surfaces and catalytic applications (Park et al., 2024; Sunada et al., 2012). For instance, Sunada et al. reported that solid-state cuprous compounds—including Cu₂O, Cu₂S, CuI, and CuCl—exhibit significantly greater antiviral activity than either silver or their cupric analogues. Notably, Cu₂O was more effective than CuO in protein adsorption and denaturation, which underpins its enhanced bioactivity (Sunada et al., 2012). In parallel, Minoshima et al. demonstrated that Cu₂O inactivates influenza A virus and bacteriophage Qβ by denaturing viral surface proteins, whereas CuO exhibited minimal antiviral activity (Minoshima et al., 2016).

Despite copper’s well-documented antimicrobial properties, real-world applications—such as ship hulls, water pipelines, and aquaculture systems—remain vulnerable to biofilm formation. This limitation often stems from insufficient copper ion release under complex environmental conditions, undermining the primary biocidal mechanism. Biofilm development involves initial microbial adhesion, colonization, and maturation into structured communities that can shield pathogens from copper-mediated killing (Shineh et al., 2023). During early-stage colonization, smoother surfaces show reduced microbial attachment, whereas in later stages, surfaces modified via shot peening exhibit enhanced antibiofilm performance compared to untreated or cold-sprayed copper, likely due to more efficient ion diffusion and localized ion accumulation. While increased surface roughness can promote ion release and improve antimicrobial efficacy, it also accelerates corrosion and may compromise long-term material durability (Razavipour et al., 2022). Moreover, excessive ion release raises biosafety concerns in certain settings. To address these challenges, multifaceted strategies have emerged. Surface nanostructuring amplifies contact-killing through enhanced reactivity and mechanical disruption (Acharya et al., 2021; Azadmanjiri et al., 2015), while alloying with elements such as Ag, Zn, or Ni introduces synergistic antimicrobial effects (Wang et al., 2016; Parimaladevi et al., 2018). Functional coatings—including Cu-based nanocomposites and polymeric modifiers—prolong efficacy and improve biocompatibility (Butot et al., 2021; Butler et al., 2023). Advanced surface engineering approaches, such as laser texturing and plasma activation, further refine oxide composition and surface energy, optimizing both antimicrobial performance and environmental stability (Walkowicz et al., 2025).

Concurrently, advancements in materials processing technologies have facilitated the precise engineering of copper-based surfaces, enabling sustained antimicrobial performance with reduced environmental footprint. High-entropy alloys (HEAs) and high-entropy coatings (HECs)—comprising five or more principal elements in near-equiatomic ratios—have emerged as promising candidates for antimicrobial applications when doped with copper. Their highly disordered atomic configurations promote homogeneous copper ion release, thereby offering tunable biocidal efficacy with minimal ecological burden (Li Z. et al., 2021). Yu et al. engineered AlCoCrFeNiCu_0.5 HEAs with uniformly dispersed Cu nanophases, mitigating phase segregation and brittleness while enhancing toughness, corrosion resistance, and antifouling performance (Yu et al., 2021). Similarly, Kuptsov et al. fabricated FeCrNiCo-(Cu) HECs using vacuum electro-spark deposition, resulting in uniform microstructures with Cu stabilized in solid solution. These coatings demonstrated excellent corrosion resistance, rapid self-passivation, and robust antibacterial activity against Bacillus cereus, underscoring their potential for deployment in aggressive marine environments (Kuptsov et al., 2023).

Additive manufacturing (AM), commonly referred to as 3D printing, has further expanded the design space for copper-based materials by enabling the fabrication of geometrically complex, porous architectures with optimized surface area and material utilization. Techniques such as selective laser melting (SLM) have yielded microporous Cu-W-Ag structures with enhanced mass transport and high surface reactivity. Notably, John et al. demonstrated that such 3D-printed architectures exhibit potent antiviral activity against SARS-CoV-2, highlighting the integration of alloy composition, topological control, and advanced processing techniques as a powerful strategy for developing next-generation antimicrobial surfaces (Robinson et al., 2021).

Nanostructured copper exhibits superior antimicrobial performance compared to its bulk counterparts, owing to its rapid ion release kinetics, elevated surface reactivity, and tunable physicochemical properties that are crucial for microbial membrane disruption and biofilm penetration (Ghezzi et al., 2022). In contrast to traditional copper alloys, nano-copper materials allow precise control over particle size, morphology, and composite integration, thereby significantly enhancing their biocidal efficacy (Molahalli et al., 2024). These advancements mark a paradigm shift into the “nano-copper era,” wherein nanoscale engineering enables unprecedented stability, biocompatibility, and broad-spectrum antimicrobial activity. Copper nanoparticles (CuNPs) have demonstrated potent antimicrobial efficacy against a wide array of pathogens, including viruses such as HIV, SARS-CoV-2, HBV, HCV, HSV, and RSV, as well as bacterial species like E. coli, S. aureus, Salmonella spp., and Streptococcus spp. (Solangi et al., 2024). Their enhanced bioactivity relative to bulk copper is primarily attributed to the higher density of grain boundaries at the nanoscale, which facilitates accelerated copper ion release and promotes the generation of ROS (Sundberg et al., 2015).

A variety of physical, chemical, and biological methods have been developed for the synthesis of copper-based nanoparticles (Crisan et al., 2021). Among these, chemical approaches, including sonochemical reduction, hydrothermal synthesis, electrochemical deposition, and chemical reduction, are the most widely adopted due to their versatility, scalability, and control over particle characteristics (Pricop et al., 2025). Pricop et al. synthesized Cu NPs via chemical reduction method, exhibited high stability, tunable size, and strong antimicrobial activity against both Gram-positive and Gram-negative bacteria (Pricop et al., 2025). Physically synthesized nanoparticles, produced by techniques such as simple ball milling, physical vapor deposition, or laser ablation, offer uniform distribution and solvent-free purity, though their application is limited by high energy demands and equipment costs (Pricop et al., 2025; Wei et al., 2020). Wei et al. synthesized CuO-biochar via simple ball milling, exhibiting strong adsorption capacity and potential for water purification (Wei et al., 2020). Hesabizadeh et al. synthesized CuO/Cu₂O NPs via pulsed laser ablation, demonstrating rapid cell wall disruption and broad-spectrum antibacterial efficacy against major foodborne pathogens at a low concentration of 3 ppm within 5 h (Hesabizadeh et al., 2023). In contrast, biological or green synthesis, utilizing plant extracts, bacteria, or fungi as reducing and stabilizing agents, offers a sustainable, cost-effective, and biocompatible route for nanoparticle production and has emerged as a promising strategy for large-scale, low-toxicity manufacturing (Chaerun et al., 2022). Nkosi et al. biosynthesized Cu NPs using a carbohydrate-based bioflocculant from Proteus mirabilis, showing potent antibacterial activity (Nkosi et al., 2025). Javid-Naderi et al. biosynthesized CuO NPs with okra extract, and further doped with silver, exhibited enhanced antimicrobial activity (Javid-Naderi et al., 2025).

Regardless of the synthesis route, copper-based nanoparticles (CuNPs) inherently exhibit robust antimicrobial properties. However, to further enhance their functional performance, stability, and specificity, surface engineering strategies are increasingly indispensable. Several advanced modification techniques have emerged as particularly effective: (1) Surface Modification and Functionalization: Tailoring the surface topography and charge—such as introducing positively charged functional groups to promote electrostatic interaction with negatively charged microbial membranes, or conjugating biomolecules to enable targeted microbial recognition—can significantly improve microbial adhesion, inactivation efficiency, and selectivity while minimizing off-target interactions. Woźniak-Budych et al. reported that cellulose acetate membranes embedded in situ with copper(I) oxide nanoparticles, stabilized by polyvinylpyrrolidone and sulfobetaine to limit copper ion leakage, exhibited markedly enhanced antibacterial activity against S. aureus and superior antifouling properties under physiological conditions, highlighting their potential in next-generation hemodialysis systems (Woźniak-Budych et al., 2024). Glutamic acid-coated copper oxide nanoparticles (GA-CuO NPs), covalently functionalized onto medical-grade silicone tubing via an oxysilane linker, demonstrated broad-spectrum efficacy, including activity against MDRpathogens (Hall et al., 2024). (2) Doping Strategies: Incorporating secondary metals such as silver or zinc into CuNPs produces nanocomposites with synergistic antimicrobial effects. Ag-doped copper nanoparticles (Cu–Ag NPs) have shown a >100-fold increase in antiviral activity against SARS-CoV-2, attributed to a sacrificial anode mechanism whereby silver accelerates copper ion release (Patlejchová et al., 2023). Similarly, co-doping CuO nanocomposites with silver and magnesium (optimal Cu:Ag:Mg ratio of 94:3:3) improved both antimicrobial potency and cytocompatibility (Kasi et al., 2024). (3) Morphology Control: Engineering specific nanostructures—such as nanowires, nanosheets, and other high-aspect-ratio forms—increases surface area and exposure of active sites, thereby enhancing antimicrobial performance. Park et al. synthesized Cu₂O nanoparticles in spherical, octahedral, and cubic shapes via chemical reduction and found that cubic Cu₂O retained the highest antimicrobial activity under prolonged thermal and humid stress, owing to its superior oxidation resistance (Park et al., 2024). (4) Defect Engineering: Introducing lattice defects into copper nanocrystals enhances their redox activity and surface reactivity. Lasemi et al. used femtosecond laser ablation to generate crystalline Cu_0.70Zn_0.30 alloy nanoparticles with abundant structural defects and periodic surface features. The resulting low-coordinated surface atoms exhibited elevated catalytic and antimicrobial activity, illustrating the synergy between crystallographic imperfections and biological functionality (Lasemi et al., 2024). (5) Single-Atom Catalysis (SACs): SACs represent a state-of-the-art strategy in which isolated copper atoms are stabilized on solid supports, offering unique electronic properties and maximized atom utilization. In antimicrobial contexts, SACs enable strong biological effects at ultralow metal concentrations, minimizing cytotoxicity while maximizing therapeutic efficacy. Zhao et al. reported that copper single atoms anchored on nitrogen-doped mesoporous carbon nanospheres efficiently generated superoxide radicals under ambient conditions, leading to broad-spectrum antibacterial activity and accelerated wound healing in vivo (Zhao et al., 2021). Lin et al. further demonstrated that SACs based on Cu anchored on graphitic carbon nitride (SA-Cu/g-C₃N₄) efficiently activated hydrogen peroxide in a photo-Fenton-like process, achieving complete inactivation of MRSA and CRAB within 5 min, and eliminating ESBL-producing E. coli and vancomycin-resistant Enterococcus (VRE) within 10 and 30 min, respectively (Lin et al., 2021).

Collectively, the integration of copper nanotechnology with advanced surface engineering has significantly expanded the toolkit for antimicrobial material development. These engineered nanostructures provide promising avenues to overcome key limitations of conventional copper-based systems. Moreover, they exhibit substantial potential in addressing antimicrobial resistance, preventing nosocomial infections, and countering emerging viral threats.

Hospitals, as dense reservoirs of pathogenic microorganisms, are especially vulnerable to nosocomial infections driven by MDR bacteria and epidemic-prone viruses. Copper-containing materials—particularly copper nanoparticle coatings—have been widely incorporated into clinical environments, including medical implants, wound dressings, dental coatings, and personal protective equipment (PPE) (Woźniak-Budych et al., 2023). Self-sanitizing surfaces coated with copper, such as hospital beds, door handles, and elevator buttons, significantly reduce pathogen survival and limit cross-contamination (Jabłońska-Trypuć et al., 2022). Copper–titanium alloys helped prevent postoperative infections (Liu et al., 2014; Zhuang et al., 2021), and copper-embedded dressings inhibited biofilm formation and combat MDR pathogens (Avatefi et al., 2024; Al-Habeeb and Al-Bishri, 2024). Copper-containing hydrogels are being explored for chronic wound healing, including diabetic ulcers (Astaneh and Fereydouni, 2024). Additionally, copper nanoparticles inhibit the proliferation of Streptococcus mutans, thereby reducing dental plaque formation (Zhang Y. et al., 2022). Copper-based filtration fibers have also proven effective in the sterilization of air and water in clinical settings (Vincent et al., 2016; Jung et al., 2022; Dixit et al., 2025). Conventional PPE offers only passive protection and poses a risk of secondary transmission during disposal. In contrast, copper-coated masks and garments actively reduce microbial burden, lowering the risk of transmission (Cortes and Zuñiga, 2020; Zhang S. et al., 2022). Notably, copper modulates immune cell functions—including helper T cells, B cells, neutrophils, natural killer (NK) cells, and macrophages—thereby potentially enhancing host antiviral defenses. This immunomodulatory effect addressed a role for copper-based nanotherapeutics in infectious disease treatment (Li X. et al., 2023). Moreover, copper ions and complexes demonstrate adjuvant-like activity, positioning them as promising candidates for vaccine formulation (Abate et al., 2022). As antibiotic resistance escalates, copper nanomaterials also emerge as viable antibiotic alternatives (Crisan et al., 2021; Parvin et al., 2025).

The COVID-19 pandemic has catalyzed demand for antimicrobial surfaces in high-traffic public areas such as hospitals, airports, transportation hubs and office buildings. Copper coatings drastically reduce the viability of viral and bacterial pathogens on surfaces, offering a practical solution for infection control (Hutasoit et al., 2020). These coatings can be applied as sprays or adhesive films, enabling long-lasting antimicrobial protection. High-power magnetron-sputtered Ta-Cu coatings on titanium alloys demonstrated tunable antibacterial activity—most notably in the TaCu-2 sample annealed at 600°C—by optimizing copper content and thermal treatment to effectively combat implant-associated pathogens such as E. coli and P. aeruginosa (Azamatov et al., 2025). Gas dynamic spray deposition of copper onto ABS plastic yields a durable antimicrobial coating for high-touch surfaces such as switch buttons, reducing microbial contamination by 2.7-fold over 22 weeks (Emelyanenko et al., 2024). Sprayable antimicrobial coatings comprising silver-loaded thiol-functionalized mesoporous silica nanoparticles (MSN-SH) immobilized on stainless steel via polyelectrolyte primers exhibit potent, broad-spectrum efficacy against bacteria and fungi under dry conditions (Bernardino et al., 2025). A pH-responsive polycaprolactone–copper peroxide (PCL-CuO₂) composite coating, fabricated via suspension flame spraying, enables controlled Cu²⁺ and H₂O₂ release under acidic conditions, achieving >99.99% antibacterial efficacy against E. coli and S. aureus, highlighting its potential for biomedical antimicrobial surfaces. (Cui et al., 2024). Innovations in superhydrophobic nanocoatings further inhibit microbial adherence, improving surface cleanliness. Electrodeposited copper surfaces coated with Teflon exhibit robust superhydrophobicity and enhanced condensation heat transfer—improving efficiency by approximately 78% and maintaining performance under mechanical stress far better than nanoneedle-structured CuO (Park et al., 2022). Addressing concerns around single-use PPE, reusable copper-infused masks have been developed that maintain breathability while actively neutralizing pathogens, thereby reducing environmental burden and operational costs (Hadinejad et al., 2023; Zhou J. et al., 2020). Zinn et al. developed a self-sterilizing copper material that rapidly inactivates a broad spectrum of pathogens within 30–60 s, offering residue-free, long-lasting antimicrobial protection ideal for integration into PPE and high-touch surfaces (Zinn et al., 2021). Jung et al. engineered a 20 nm copper film on polypropylene filters via vacuum deposition and oxygen ion pretreatment, enabling KF94 masks to inactivate over 75% of SARS-CoV-2 while retaining high filtration performance, advancing next-generation protective materials (Jung et al., 2021). Moreover, antimicrobial copper-based paints and coatings for walls and glass surfaces are under active development, offering the potential to reduce disinfection frequency and significantly lower labor costs in facility maintenance. Early dark-toned formulations have evolved into light-colored or transparent variants, such as the diatomite/Cu₂O/CPT composite by Zou et al. (2024), and the transparent glass-ceramic copper coatings developed by Culpepper et al. (2025), both exhibiting strong and broad-spectrum antiviral activity with commercial promise. Golovchak et al. developed a durable, low-cost Cu–Sr phosphate glass that eradicates S. aureus within 24 h at low concentrations while remaining biocompatible, offering broad potential for antimicrobial medical and public-use coatings (Golovchak et al., 2025).

Textile-based vectors of disease transmission are also a concern. Traditional antimicrobial textiles suffer from rapid functional degradation caused by repeated washing and perspiration exposure, and may also pose toxicity risks (Broadhead et al., 2021). Nanotechnology now allows for the durable integration of copper nanoparticles into fabric fibers, preserving antimicrobial efficacy after more than 20 washing cycles (Mohamed et al., 2021; Hillyer et al., 2022). This advancement has enabled the development of medical textiles, including antimicrobial gauze, bandages, surgical gowns, and wipes. Cellulose-based fabrics, inherently susceptible to bacterial contamination, have been transformed into superhydrophobic, antibacterial textiles with enhanced resistance to pathogen adhesion through surface micro/nanostructuring and chemical modifications (Zhou H. et al., 2023; Alashkar et al., 2024). Priyanka et al. engineered hydrophobic nanocoated cotton fabrics by integrating mussel-inspired polydopamine, graphene oxide, and copper compounds, resulting in textiles that effectively repel fluids and inhibit bacterial growth (Prabhakar et al., 2022). Han et al. fabricated superhydrophobic copper nanoparticle-coated cotton fabrics via sonochemical deposition in alkaline media, achieving 145° water contact angles and effective antibacterial performance through Lotus-inspired micro/nano-scale surface structuring (Han and Min, 2020). Chen et al. fabricated superhydrophobic copper-coated cotton fabrics featuring micro/nano coral-like architectures via self-assembly and spray deposition, achieving a water contact angle of 161° alongside remarkable abrasion resistance, corrosion durability, and intrinsic conductivity (Chen et al., 2022). Investigating the influence of weave structure on inkjet printing quality, Sandu et al. demonstrated that electroless copper-plated textiles activated by inkjet-printed Cu/Ag catalysts along the weft exhibited durable antipathogenic efficacy—including virucidal activity against HCoV-OC43, HCoV-229E, influenza A (H1N1), and rotavirus A—while maintaining low cytotoxicity and year-long antibacterial stability (Sandu et al., 2025). Muhammad-Amir et al. further revealed that green-synthesized copper-treated cotton fabrics showed ∼60% higher tensile strength in the warp and ∼20% in the weft, with improved dye uptake and fastness, highlighting the key role of dyeing direction and fiber orientation in enhancing textile performance (Amir et al., 2023). To further enhance the safety and wearability of copper nanoparticles embedded in textile fibers, recent studies have explored strategies such as core–shell encapsulation (Komeily-Nia et al., 2019; Kuo et al., 2024), surface passivation with biocompatible polymers to reduce cytotoxicity (Matijaković Mlinarić et al., 2024; Calais et al., 2024), integration of metal–organic frameworks (MOFs) for multifunctional wearable systems (Eagleton et al., 2022; Eagleton et al., 2023; Xiao et al., 2024), precise nanoparticle immobilization through covalent bonding or in situ synthesis within fiber matrices, aimed at minimizing environmental leaching and dermal exposure (Xiao et al., 2024; Jalali et al., 2024; Huang et al., 2022; Tan X. et al., 2024; Bayisa et al., 2024; Zhao Z. et al., 2024), as well as green nanoengineered fabrics for improved biocompatibility (Meganathan and Ramalingam, 2024; Yu et al., 2025; Asmat-Campos et al., 2023). Additionally, time-dependent release kinetics (Ferrer-Vilanova et al., 2025), cytocompatibility assays on human skin cell lines (Świerczyńska et al., 2024), and long-term stability (more than 50 washing cycles) under washing and wear conditions have become standard evaluation metrics (Wen et al., 2024), ensuring both efficacy and biosafety for clinical and consumer applications.

Antimicrobial packaging plays a critical role in ensuring food safety by preventing microbial contamination and extending shelf life. Saravanakumar et al. developed a cellulose nanowhisker–sodium alginate (CNW–SA) composite film loaded with CuO nanoparticles (NPs), which exhibited potent antibacterial activity against S. aureus, E. coli, Salmonella spp., Candida albicans, and Trichoderma spp. (Saravanakumar et al., 2020). Zhao et al. developed polylactic acid (PLA)/halloysite–Cu²⁺ composite nanofiber membranes exhibiting superior biocompatibility, mechanical robustness, thermal stability, hydrophobicity and antibacterial efficacy, markedly enhancing strawberry preservation (Zhao X. et al., 2024). Shi et al. demonstrated that a nanocopper/polypropylene composite conferred enhanced antioxidant and antimicrobial properties, significantly extending the freshness and shelf life of packaged foods (Shi et al., 2021). The green-synthesized copper nanoparticles offer an economically feasible and non-toxic approach in food packaging. Kumari et al. demonstrated that Argemone mexicana–mediated green synthesis of Cu NPs within κ-carrageenan films produces biodegradable packaging with enhanced thermal stability, mechanical robustness, water-vapour and UV-barrier performance, and potent antibacterial activity against S. aureus and E. coli, extending grape and cottage cheese shelf life to 12 and 7 days, respectively (Kumari et al., 2024). Moldovan et al. engineered PLA/Proviplast composites incorporating 0.5–1.5 wt% grape pomace or 2–8 wt% PEG600-stabilized Cu particles, which function as bioactive plasticizers—reducing Tg, Tcc and Tm and modestly lowering thermal stability—while significantly boosting elongation at break and modulus, thereby creating flexible, eco-functional materials that valorize agricultural waste for sustainable active food packaging (Moldovan et al., 2024). Che et al. developed quercetin–copper nanoparticles with strong antioxidant and antibacterial activity, which effectively reduced weight loss and extended the shelf life of Shine Muscat grapes (Che et al., 2025). Although copper nanoparticles confer functional benefits to food packaging, their potential migration into food poses safety risks, warranting comprehensive future safety evaluations before commercial adoption. Copperprotek USA’s FDA/FSIS GRAS-approved 100% copper microparticles—the first copper salt-based additive cleared for food-packaging applications—are entering industrial-scale testing with a major U.S. packaging firm, enabling integration into animal-based products from 2025 and marking a milestone in antimicrobial, shelf life–extending packaging technology (Copperprotek, 2025). Moreover, in food processing environments, non–food-contact surfaces—such as drains, transport carts and equipment casings—harbour aerosol-transmissible pathogens like norovirus and hepatitis a virus, which copper-based coatings can efficiently inactivate to prevent indirect contamination (Camacho et al., 2023).

Beyond healthcare and food safety, copper-based systems are increasingly applied across agriculture, aquaculture, marine environments, and electronic industries. In animal husbandry, copper salts and nanoparticle formulations are used as bactericides, algicides, insect repellents, and preservatives (Kanhed et al., 2014). Möhrke et al. showed that twin-wire arc-sprayed copper coatings—using compressed air or nitrogen—achieved a 99% reduction in pathogenic bacteria common in broiler farming (E. coli, S. aureus, Escherichia cecorum) compared to uncoated steel, with post-treatments such as cold plasma and TIG arc further enhancing antibacterial efficacy and durability (Möhrke et al., 2024). Cu NPs—serving as growth promoters, antioxidants, and antibiotic alternatives—hold promising potential for broad biotechnological applications (Sharif et al., 2021; Qadeer et al., 2024; Nechitailo et al., 2025). However, the reported toxicity of Cu NPs necessitates further studies to elucidate their mechanistic effects and safety in animal husbandry (Sabry et al., 2021).

In aquaculture, copper-coated or alloyed equipment—tanks, pipes, filters, enclosures—minimizes biofouling and cross-species transmission of pathogens, aiding in the containment of AMR. Liu et al. reported that in situ growth of Cu-MOF films on alkali-heat-treated Ti-6Al-4V produced bioactive coatings with strong antibacterial and algicidal activity (Liu and Gao, 2024). Ponurko et al. reported that copper-containing glassy phosphate compositions (CGPCs) form continuous phosphate films and release Cu²⁺ ions in aqueous environments, synergistically inhibiting microbial growth by blocking oxygen access and disrupting biological activity, highlighting their potential for broad-spectrum water treatment applications (Ponurko et al., 2023). Ilkhas et al. developed a Cu-doped ZnO/reduced graphene oxide nanocomposite synthesized in one step that efficiently degrades antibiotics and inactivates resistant bacteria in shrimp aquaculture water (Ilkhas et al., 2024).

In crop science, copper-based nanomaterials serve as both essential micronutrients and antimicrobial agents. These nanomaterials represent a promising avenue for improving crop yield and managing plant diseases, functioning as nanofertilizers, nanoregulators, nanostimulants, and nanopesticides to enhance plant growth, stress resistance, and seed germination. In particular, the green synthesis of copper-based nanoparticles enables environmentally sustainable agricultural strategies (Amin and Aziz, 2025). Martins et al. demonstrated that controlling Cu²⁺ ion release from CuO-based nanofertilizers using plant growth regulator–derived ionic liquids significantly enhanced photosynthetic efficiency, biomass accumulation, and CO₂ capture in Nicotiana tabacum, highlighting the pivotal role of ion dissolution kinetics in the rational design of sustainable nanofertilizers (Martins et al., 2024). Notably, copper nanoparticles biosynthesized using endophytic fungi have been shown to possess strong biocidal activity and to stimulate plant innate immune responses, offering new biocompatible tools for advancing sustainable crop production (Selim et al., 2025).

In marine engineering, HEAs and copper-based coatings are widely utilized on ship hulls to mitigate biofouling, reduce hydrodynamic drag, and prevent corrosion (Yu et al., 2021; Kuptsov et al., 2023). Zhou et al. engineered Cu–Ag HEAs exhibiting enhanced Cu⁺/Cu²⁺ ion release, alongside superior mechanical strength, corrosion resistance, and broad-spectrum antimicrobial activity—achieving 99.9% bacterial inhibition and approximately 99% deactivation of SARS-CoV-2 (Zhou et al., 2024). Ding et al. reported that Cu₂O-containing marine coatings based on poly (lauryl methacrylate)-b-poly (2-(N,N-dimethylamino)ethyl methacrylate) copolymers enabled controlled copper ion release, significantly improving both bactericidal and antifouling efficacy for sustainable marine applications (Wang et al., 2025). Li et al. functionalized three-dimensional porous Cu₂O nanoparticles (3DNP-Cu₂O/rGOx@R-Gel) to promote sustained Cu⁺ ion release, achieving potent antibacterial and antifouling performance while minimizing overall copper ion leaching. The incorporation of reduced graphene oxide (rGO) and R-Gel facilitated the in situ reduction of Cu²⁺ to Cu⁺ and enhanced system stability under marine conditions (Li H. et al., 2023). Furthermore, biomimetic copper nanostructures, mimicking naturally antimicrobial surface morphologies, have been developed to enhance antifouling efficacy and material durability, with potential applications extending across marine and biomedical domains (Ruggeri et al., 2024; Li et al., 2024; Chen et al., 2021). A notable example is a bioinspired shark-skin-like antimicrobial surface fabricated on titanium alloy via a single-step wire electrical discharge machining (WEDM) process, which achieved 93% bacterial inhibition, further enhanced to 98.4% after acid etching, along with excellent bioactivity—underscoring its applicability in marine environments (Zhang et al., 2023). Liu et al. fabricated thermally stable, wood-inspired copper surfaces using metallic glass templating techniques, achieving robust hydrophobicity and anti-icing performance under extreme environmental conditions. These surfaces highlight the potential of structurally engineered copper materials for long-term use in harsh marine and shipbuilding scenarios (Liu et al., 2021).

Furthermore, copper-based coatings are increasingly integrated into antimicrobial glass and plastic surfaces of high-touch electronics—such as smartphones, laptops, and tablets—to mitigate microbial adhesion and reduce the risk of fomite-mediated infections (Boas and Reches, 2021; Gamonchuang et al., 2024). Tian et al. developed amine–carboxyl (AC) co-modified Cu-AC nanoparticles with high monodispersity and antioxidant capacity, which synergistically enhance the antibacterial, thermal, and mechanical properties of polypropylene composites, achieving up to 99% antimicrobial efficacy and offering broad potential in thermoplastic applications for frequently handled surfaces (Tian et al., 2024). Golovchak et al. reported a cost-effective and durable Cu-containing strontium-modified phosphate glass with potent antibacterial activity against S. aureus, highlighting its potential in antimicrobial glass technologies (Golovchak et al., 2025). Jiang et al. demonstrated that Cu⁺ -doped ion-exchanged glass exhibited an enhanced mechanical strength, and sustained antimicrobial activity via controlled surface incorporation of copper (Jiang et al., 2024). In addition to their antimicrobial utility, copper-based materials exhibit excellent catalytic activity, making them attractive candidates for environmental remediation (Bonthula et al., 2023). For instance, Vinothkanna et al. demonstrated that biogenically synthesized copper oxide nanoparticles derived from Rubia cordifolia bark extract possess potent antibacterial, antioxidant, larvicidal, and photocatalytic properties (Vinothkanna et al., 2023). Similarly, Kumar et al. developed Co/Cu-doped hematite nanoparticles using Azadirachta indica leaf extract, achieving tunable crystalline and magnetic properties alongside robust photocatalytic and antioxidant activity—emphasizing their promise as eco-friendly agents in environmental clean-up applications (Kumar et al., 2024).

Several ongoing clinical and field trials are currently investigating the real-world efficacy of copper-based materials. These include studies on copper’s impact on antimicrobial resistance in ICUs (CUPRIC, NCT04873557), its role in wound healing (NCT01565798, NCT02351895, NCT03284749, NCT05215730), and its effectiveness in reducing healthcare-acquired infections in pediatric ICUs (NCT01678612). Additionally, copper’s use in agriculture is being tested in field trials targeting Pseudomonas syringae in Nicotiana tabacum production (Webb and Bailey, 2024). These trials provide valuable data supporting copper’s antimicrobial applications in clinical and public settings, as well as in agriculture.