Nanomaterial strategies for antibiotic-resistant infections: Mechanistic frameworks, rational design, and clinical translation

Abstract

Antimicrobial resistance drives substantial global morbidity and mortality, yet conventional antibiotics often fail in rapidly disseminating planktonic bloodstream infections or sepsis, intracellular reservoirs with limited drug exposure, and biofilm- or device-associated infections that are prone to relapse. Nanomaterials provide an interface-focused, multitarget approach that combines direct antibacterial activity, controlled delivery, and host modulation. Here, we evaluate antibacterial nanomaterials according to the major biological barriers encountered during the infection cascade, including surface precolonization, adhesion and invasion, biofilm maturation, intracellular persistence, and tissue spread or relapse. These barriers correspond to material functions such as membrane permeabilization, proton-motive-force and efflux modulation, matrix penetration and remodeling, intracellular release, and host-directed immunomodulation. Current strategies broadly include intrinsically antibacterial materials and nanocarriers that enhance the activity of existing antibiotics through controlled release or externally triggered activation. Evidence is evaluated through quantitative readouts linking mechanisms to outcomes, including bacterial burden reduction, biofilm remodeling, intracellular clearance, and relapse-related endpoints. We also discuss diagnostic and image-guided systems, together with translational requirements such as reproducible manufacturing, controlled ion or reactive oxygen species release, predictable protein-corona behavior, infection-site pharmacokinetics, and regulatory alignment beyond the in vitro minimum inhibitory concentration.

Graphical abstract

Conceptual framework for nanomaterial strategies addressing antibiotic failure.The scheme links major failure contexts of conventional antibiotics—planktonic sepsis, intracellular persistence, and biofilm/device-associated relapse—to nanomaterial-enabled interventions, including intrinsic antibacterial activity, potentiation of legacy antibiotics, and host-directed modulation, together with key translational gates such as exposure control, CMC/QbD, in vivo pharmacokinetics, and regulatory alignment.

1. Introduction

Antimicrobial resistance (AMR) has moved from projection to measurement and is now a major contributor to global morbidity and mortality [[1], [2], [3]]. Drug-resistant bacterial infections burden all tiers of care from intensive care units to outpatient clinics, and the line between hospital-acquired and community-acquired disease is becoming increasingly porous [4]. High-risk organisms prioritized by international and national agencies, such as carbapenem-resistant Acinetobacter baumannii, multidrug-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, and multidrug-resistant Mycobacterium tuberculosis, illustrate a convergent reality: resistance rates are rising, therapeutic options are constrained, and invasive syndromes such as bloodstream infection and ventilator-associated pneumonia carry excess mortality. The magnitude of the AMR reflects not only pathogen genetics but also systemic clinical and innovation bottlenecks. Recent WHO surveillance further quantifies this pressure in routine care: one in six laboratory-confirmed common bacterial infections worldwide in 2023 was resistant to antibiotic treatment, with more than 40% of Escherichia coli and more than 55% of Klebsiella pneumoniae resistant to third-generation cephalosporins, while global carbapenem resistance in Acinetobacter spp. reached 54.3% [5]. Consistent with these patterns, the 2024 WHO Bacterial Priority Pathogens List continues to rank carbapenem-resistant A. baumannii, carbapenem-resistant and third-generation cephalosporin-resistant Enterobacterales, and rifampicin-resistant Mycobacterium tuberculosis in the critical tier, with antibiotic-resistant Pseudomonas aeruginosa and Staphylococcus aureus remaining high-priority threats. Delayed diagnostics, uneven access to effective agents, and a slow innovation pipeline amplify the clinical impact of resistance [6,7].

At its core, treatment failure reflects a combined evolutionary, ecological, and pharmacologic problem [8]. Selection during treatment can rapidly enrich resistant subpopulations when pressure is concentrated on a single mechanism. The structure and physiology of bacterial communities generate tolerance that routine tests do not capture and that sustains recurrence [9]. Importantly, tolerance and persistence are phenotypic states that are distinct from genetic resistance but equally consequential in clinical relapse. Clinical dosing is limited by toxicity and by the difficulty of delivering adequate concentrations to sequestered sites such as abscesses and necrotic tissue [[10], [11], [12]]. These realities erode the expectation that a single drug directed at a single target will yield a uniform outcome.

Nanomaterials offer an interface-centered therapeutic approach that is inherently multitarget. High surface-to-volume ratios, controllable sizes and shapes, and programmable surface chemistry enable nanomaterials to interact with bacterial envelopes, biofilm matrices, and host immune components in ways that can extend beyond the functional limitations of conventional small molecules [13,14]. Two design logics anchor current efforts. One method exploits intrinsic antibacterial activity, including membrane permeabilization by cationic polymer architectures, catalytic generation of reactive oxygen species, and targeted interference with key bacterial processes [15]. The other uses nanocarriers as precision delivery systems to increase the solubility and stability of existing antibiotics, overcome permeability and efflux barriers, and confer site selectivity through stimuli-responsive release tuned to local acidity, bacterial enzymes, or endogenous oxidative stress; external inputs such as light, ultrasound, or magnetic fields add spatial and temporal control [16,17]. Several platforms also engage in host-directed pathways by modulating macrophage polarization, neutrophil recruitment, extracellular trap formation, complement activity, and cytokine programs, thereby coupling bacterial killing with calibrated inflammation and tissue repair [18].

Purpose and scope. We position this Review around an infection cascade and a set of auditable design modules that link mechanism to outcome. We assess antibacterial nanomedicine via quantitative readouts, including log reductions in bacterial burden, changes in biofilm architecture, intracellular exposure, and survival or relapse endpoints, and we evaluate evidence along a translational ladder from high-throughput screens to disease-relevant matrices, animal models, and early clinical studies. This Review is organized into four parts: mechanistic foundations; material classes and design rules; nanodiagnostics and theranostic integration; and applications in models and early clinical experience. A structured PubMed search supplemented by reference screening and backward/forward citation tracking was used to identify eligible studies; the study selection workflow is summarized in Fig. S1 (Supplementary Methods for full details). Vaccines and monoclonal antibodies are considered only when they are integrated into a nanomaterial platform that alters exposure, selectivity, or activation. This cascade-based and outcome-linked organization distinguishes this Review from material-centered summaries by converting antibacterial nanomaterial design into a decision framework that connects biological barriers, engineering modules, quantitative efficacy metrics and translational risk.

2. Current status and limitations of treatment for antibiotic-resistant bacteria

2.1. Global epidemiology of antibiotic-resistant bacteria

In 2021, bacterial antimicrobial resistance was estimated to directly cause 1.14 million deaths and to be associated with 4.71 million deaths worldwide, underscoring a burden that remains comparable to or greater than that of many other major infectious diseases [19]. Adverse consequences of antimicrobial resistance are now seen across both health-care-associated and community-associated infections throughout the life course, and the 2024 WHO Bacterial Priority Pathogens List further highlights the growing importance of resistant pathogens in community settings, underscoring how the historical boundary between hospital-acquired and community-acquired infections is becoming increasingly blurred [20]. The 2024 World Health Organization Bacterial Priority Pathogens List ranks twenty-four pathogens across fifteen families into critical, high and medium tiers; carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Enterobacterales are considered critical, whereas carbapenem-resistant Pseudomonas aeruginosa is classified as high priority because therapeutic options are scarce and case fatality is high. MRSA and vancomycin-resistant Enterococcus faecium remain major contributors to the global burden, and rifampicin-resistant Mycobacterium tuberculosis is also included in the critical tier [21]. Recent surveillance has also documented marked increases in metallo-β-lactamase–producing carbapenem-resistant Enterobacterales, including NDM, with implications for empiric therapy and infection control [22].

2.2. Key limitations and drivers of treatment failure

Incremental additions to the antibiotic armamentarium have broadened options but have not fully overcome persistent drivers of poor outcomes. New β-lactam–β-lactamase inhibitor combinations—ceftazidime–avibactam, meropenem–vaborbactam, and imipenem–relebactam—and the siderophore cephalosporin cefiderocol have broadened options against carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. For Gram-positive pathogens, vancomycin, daptomycin and linezolid remain the principal agents for MRSA and vancomycin-resistant enterococci, and polymyxins are still used as salvage therapies for recalcitrant Gram-negative disease [21]. However, four constraints keep clinical outcomes fragile. Resistance can emerge under treatment pressure, including treatment-emergent resistance to newly approved agents such as cefiderocol in Acinetobacter baumannii [23,24]. Biofilm-linked tolerance disconnects laboratory susceptibility from the clinical response through matrix barriers, altered metabolic states, persister subpopulations and active efflux, which sustains relapse in chronic and device-associated infections [1,25]. Pharmacokinetic and toxicity constraints narrow the therapeutic exposure window for last-resort agents. A meta-analysis of randomized controlled trials revealed that approximately 36.2% (95% CI, 23.3% to 51.3%) of colistin users experienced nephrotoxicity [26], whereas multiple studies have indicated that drug penetration into abscesses, necrotic tissue, and hypoperfused areas may fail to consistently achieve pharmacodynamic targets [27,28]. The innovation pipeline also lags from the epidemiologic need; the World Health Organization reported ninety-seven antibacterial products in clinical development as of 2023; among the 32 antibiotics targeting priority pathogens, only 12 met at least one innovation criterion, and only 4 were active against at least one WHO critical pathogen [29,30]. These realities define the design brief for next-generation strategies: distributing antimicrobial pressure across multiple targets, reaching protected niches, including biofilms and intracellular reservoirs, and achieving site-selective, time-controlled action at infected interfaces. Therefore, in the following section, we systematically examine the key nodes at each stage of the infection cascade, discuss their theoretical basis as potential intervention targets, and review the latest research progress. For quick reference, the clinically consequential resistant pathogens, dominant resistance mechanisms, clinical impact, and nanomaterial-relevant intervention features are summarized in Box 1. From a nanomaterial design perspective, these priority pathogens share several intervention-relevant vulnerabilities. Gram-negative pathogens, such as carbapenem-resistant A. baumannii, carbapenem-resistant Enterobacterales, and carbapenem-resistant P. aeruginosa, commonly exhibit outer-membrane permeability barriers, active efflux, and enzyme-mediated antibiotic inactivation, which may be addressed by membrane-permeabilizing nanomaterials, efflux-attenuating combinations, and exposure-sustaining or enzyme-shielding carriers. Biofilm-forming organisms, particularly MRSA, P. aeruginosa, and device-associated pathogens, present matrix-related barriers that can be targeted by DNase-loaded, enzyme-responsive, or matrix-remodeling nanoplatforms. Intracellular or mucosa-associated pathogens, including M. tuberculosis, Salmonella, Shigella, N. gonorrhoeae, S. pneumoniae, and H. influenzae, create additional opportunities for macrophage-targeted, mucus-penetrating, inhalable, or locally retained nanocarriers. These nanosusceptibility features provide a mechanistic basis for matching nanomaterial functions to pathogen biology rather than treating priority pathogens as a purely epidemiological list.

Box 1 | Priority antibiotic-resistant pathogens at a glance.

Critical priority (WHO, 2024)

Carbapenem-resistaAcinetobacter baumanniinii (CRAB) Mechanisms include carbapenemase production, reduced permeability and active efflux. Clinical impact includes ICU-associated outbreaks and ventilator-associated pneumonia; cefiderocol resistance during therapy has been reported [30]. Carbapenem-resistant Enterobacterales (CRE) Mechanisms include KPC, NDM and OXA-48-like carbapenemases, often with porin loss and efflux. Clinical impact includes bloodstream and other invasive infections with high mortality, especially in severe cohorts [31]. Third-generation cephalosporin-resistant Enterobacterales (3GCRE) Mechanisms include extended-spectrum β-lactamases and/or AmpC production, often with additional porin changes. Clinical impact includes common invasive and urinary infections that complicate empirical therapy and increase carbapenem use [6]. Rifampicin-resistaM. tuberculosissis (RR-TB) Rifampicin resistance is primarily associated with mutations in the rpoB rifampicin-resistance determining region, whereas katG and inhA alterations are more closely linked to isoniazid resistance and are relevant when MDR-TB is considered. In 2023, WHO estimated MDR/RR-TB in 3.2% of new TB cases and 16% of previously treated TB cases globally [32].

High priority

Methicillin-resistanStaphylococcus aureuseus (MRSA) mecA-mediated PBP2a confers broad β-lactam resistance; MRSA caused more than 100,000 attributable AMR deaths in 2019 [33]. Vancomycin-resistaEnterococcus faeciumium (VREfm) vanA/vanB operons encode D-Ala–D-Lac substitution, with bloodstream and urinary tract infections that are difficult to treat in vulnerable hosts [34]. Carbapenem-resistaPseudomonas aeruginosaosa (CRPA) Mechanisms include intrinsic low permeability, RND-family efflux and metallo-β-lactamases. Clinical impact includes severe pneumonia and bloodstream infection, with diminished activity of some β-lactam/β-lactamase inhibitor combinations in carbapenemase-producing subsets [34,35]. Fluoroquinolone-resistant Salmonella Typhi Mechanisms include QRDR mutations in gyrA and parC, with additional plasmid-mediated quinolone resistance reported in some isolates. Clinical impact includes enteric fever with reduced fluoroquinolone efficacy and increasing pressure on alternative therapies [36]. Fluoroquinolone-resistant Shigella spp. Mechanisms include stepwise QRDR mutations and, in some strains, plasmid-mediated quinolone resistance determinants. Clinical impact includes dysenteric and other enteric infections with reduced oral treatment options and increasing outbreak-management difficulty [37]. Fluoroquinolone-resistant nontyphoidal Salmonella Mechanisms include QRDR mutations and plasmid-mediated quinolone resistance determinants. Clinical impact includes foodborne and invasive infection with reduced fluoroquinolone utility and greater reliance on alternative agents [36]. Third-generation cephalosporin- and/or fluoroquinolone-resistant Neisseria gonorrhoeae Mechanisms include mosaic penA alleles with additional porin and efflux-associated changes for cephalosporin resistance, and gyrA/parC mutations for fluoroquinolone resistance. Clinical impact includes gonorrhea with narrowing treatment options and documented failures with extended-spectrum cephalosporins in some settings [38].

Medium priority

Group A streptococci, macrolide-resistant Mechanisms include target-site methylation mediated by erm genes and active efflux mediated by mef-associated determinants. Clinical impact includes pharyngeal, skin/soft-tissue and invasive infections, with particular concern in vulnerable populations and settings with limited access to alternative therapy [6]. fStreptococcus pneumoniaeiae, macrolide-resistant Mechanisms include ribosomal methylation mediated by erm(B) and macrolide efflux mediated by mef(A/E) determinants. Clinical impact includes community-acquired pneumonia, otitis media and invasive pneumococcal disease, especially in children and older adults [6]. fHaemophilus influenzaezae, ampicillin-resistant Mechanisms include β-lactamase production and altered PBP3 associated with ftsI mutations, including β-lactamase-negative ampicillin-resistant lineages. Clinical impact includes respiratory tract and invasive infections that complicate empirical therapy, particularly in children and in resource-limited settings [6]. Group B streptococci, penicillin-resistant Mechanisms include altered penicillin-binding proteins, particularly PBP2X, associated with reduced penicillin susceptibility and resistance. Clinical impact includes neonatal, maternal and invasive adult infections, warranting close surveillance in vulnerable populations [6].

Note:Critical priority,High priority,Medium priority.

3. The infection cascade: stages and intervention nodes

3.1. Precolonization of surfaces

Before stable colonization, bacteria encounter conditioning films on tissues and devices, where early protein adsorption and ionic screening determine subsequent attachment. Surface conditioning is dynamic and influenced by shear stress, host inflammatory exudates, and evolving protein coronas. In vivo, corona formation may also mask targeting ligands, alter surface charge, accelerate opsonization or macrophage clearance, and reduce lesion-level accumulation. The intervention node at this stage is the control of the nanobio interface to prevent fouling and reduce the probability of initial capture. Hydration-layer chemistries such as zwitterionic or polysaccharide brushes, low-adhesion topographies with submicron features, and ultrathin coatings that minimize nonspecific protein adsorption suppress adhesive coronas. Contact-active surfaces that present cationic or catalytic motifs add a short-range killing component without bulk release [39].

3.2. Adhesion and invasion

Once near the surface, pathogens use microbial surface components that recognize adhesive matrix molecules (MSCRAMMs) and cell wall anchoring systems to stabilize contact and invade host cells. The intervention node is the blockade of ligand–receptor engagement and interruption of LPXTG sorting. These mechanisms are particularly relevant to gram-positive pathogens. Multivalent nanostructures that display fibrinogen-, fibronectin- or collagen-mimetic ligands may act as competitive binders and reduce attachment to tissue and device interfaces. Inhibitors of sortase-mediated anchoring, together with wall teichoic- or lipoteichoic-targeting chemistries, can reduce effective adhesin display or adhesion efficiency on the bacterial envelope [40].

3.3. Microcolony formation and biofilm maturation

Microcolonies mature into biofilms encased in extracellular polymeric substances that hinder diffusion, support metabolic tolerance, and shelter persister subpopulations. The intervention node combines physical penetration with matrix remodeling and quorum modulation. NPs with suitably small hydrodynamic diameters and tailored charge or hydrophobic patterns can traverse interstitial pores, whereas enzyme-decorated or redox-active platforms cleave polysaccharides and extracellular DNA or generate local oxidative stress that loosens the matrix. Stimulus-responsive carriers release payloads in acidic, protease-rich or oxidizing microenvironments and resensitize biofilm cells to legacy antibiotics [41].

3.4. Intracellular persistence

Many pathogens persist inside macrophages, epithelial cells or osteoblasts, where antibiotic exposure is attenuated. The intervention node is intracellularly targeted delivery with controlled release and, when necessary, endosomal escape [42]. Carriers tuned to acidic endolysosomal pH or to infection-responsive redox cues enable activation at the site of residence. Compartment-directed motifs can steer exposure toward specific intracellular compartments, and membrane-active peptides or pH-switchable lipids can facilitate endosomal escape when cytosolic delivery is needed. Host-directed features that calibrate macrophage responses or increase bacterial clearance complement direct killing.

3.5. Tissue spread and relapse

Following partial control, residual bacteria in abscesses, necrotic tissue or poorly perfused compartments can sustain infection and contribute to relapse. The intervention node is engineering spatial pharmacokinetic gradients at the infected interface. In situ-forming depots, mucoadhesive or mucopenetrating carriers, and materials responsive to ionic strength or pH may help maintain effective concentrations where the microcirculation is limited. External actuation by light, ultrasound or magnetic fields adds spatiotemporal control when anatomical access allows it (Fig. 1). To clarify how each stage of the infection cascade corresponds to a specific nanomaterial design logic, we summarize the major biological barriers, design modules, and representative mechanisms in Table 1.

Fig. 1.

| Framework linking the infection cascade to engineered design modules and critical translation gates.

Table 1.

Mapping infection stages to nanomaterial design modules and representative mechanisms.

Infection stage	Main biological barrier	Nanomaterial design module	Representative mechanism
Surface precolonization	Conditioning films and early bacterial capture	Antifouling and contact-active interfaces	Zwitterionic or hydrated coatings reduce nonspecific adsorption; cationic or catalytic motifs provide short-range killing
Adhesion and invasion	Adhesin-mediated attachment and host-cell entry	Receptor blockade and ligand competition	Multivalent ligands, sortase-interfering designs, and wall-teichoic-acid-targeted chemistries reduce bacterial attachment
Biofilm maturation	EPS barrier, hypoxia, metabolic heterogeneity	Matrix penetration and remodeling	Small or charge-tuned particles, DNase I, dispersal enzymes, redox-active platforms, and stimulus-responsive carriers loosen EPS and improve antibiotic access
Intracellular persistence	Phagolysosomal sequestration and reduced antibiotic exposure	Intracellular targeting and triggered release	Macrophage-targeting ligands, pH-sensitive carriers, endosomal escape modules, and redox-responsive release improve intracellular clearance
Tissue spread and relapse	Abscesses, necrotic tissue, and poor perfusion	Local depot and externally controlled activation	Hydrogels, mucoadhesive carriers, magnetic, acoustic, or photothermal activation sustain local exposure and reduce relapse risk

The left panel summarizes key stages of the infection cascade, from precolonization and adhesion/invasion to biofilm maturation, intracellular persistence, and tissue spread/relapse. The right panel shows corresponding nanomaterial-enabled design modules, including antifouling/repulsion, receptor blockade, matrix penetration, and intracellular delivery with sustained release. The bottom panel highlights tunable design levers—size, shape, zeta potential, surface functionalization, and responsiveness—that can be adjusted to optimize performance across stages.

4. Antibacterial mechanism of nanomaterials

Following the infection-cascade framework established above, this section dissects the principal mechanistic modules through which nanomaterials act at the bacterial, biofilm, intracellular, and host-interface levels. Antimicrobial nanomaterials have emerged as promising strategies to overcome the multifaceted challenges posed by pathogens, biofilm matrices, and host interactions. These nanomaterials act on microbes, the surrounding matrix, and the host. Their effects can be organized into five broad, partly overlapping mechanisms: membrane disruption and increased permeability; bioenergetic and efflux-related sensitization; penetration and remodeling of the biofilm matrix; targeted molecular interference; and host-directed immunoregulation (Fig. 2A).

Fig. 2.

Mechanistic modules, engineering principles, and translational evaluation of antibacterial nanomaterials. (A) Mechanistic modules of antibacterial nanomaterials. At the infection interface, nanomaterials can act at multiple resistance failure points, including membrane barriers, efflux pumps, enzymatic drug inactivation, biofilm-associated protection, and resistance-related molecular targets. These effects can be organized into five broad and partly overlapping mechanistic modules: (1) membrane permeabilization and envelope damage, which increase bacterial membrane permeability; promote pore formation; and facilitate antibiotic entry while causing ATP and K⁺ leakage; (2) bioenergetic control and efflux attenuation, in which nanomaterials disrupt the proton motive force (PMF), interfere with respiration, inhibit efflux activity, and increase intracellular drug retention; (3) biofilm matrix penetration and remodeling, which promote extracellular polymeric substance (EPS) penetration, cleavage of eDNA and polysaccharides, loosening of biofilm architecture, and improved antibiotic access to embedded bacteria; (4) targeted molecular interference, which includes ligand-directed binding, D-Ala–D-Ala recognition, aptamer-guided localization, and interference with defined genes, mRNAs, or protein targets; and (5) host-directed immunoregulation, in which nanomaterials enhance phagocytosis, rebalance cytokine responses, support innate immune function, and promote tissue repair and infection resolution. (B) Design principles and engineering considerations for antibacterial nanomaterials. Major nanomaterial classes include metal/metal oxide nanoparticles, hybrid nanomaterials, carbon-based nanomaterials, liposomes/micelles, and polymeric nanoparticles. Their antibacterial performance can be tuned through physicochemical properties, such as size, shape, surface charge, and cellular uptake/penetration, as well as through surface functionalization strategies, including targeting ligands, antimicrobial or antibiotic payloads, stealth polymers for immune evasion and stability, and stimuli-responsive coatings. Together, these design variables help optimize efficacy and biocompatibility. (C) Translational evaluation ladder for antibacterial nanomaterials. Development typically progresses from preclinical research, including in vitro and in vivo evaluation, to regulatory approval pathways involving safety and efficacy testing and GMP manufacturing and then to clinical applications such as topical/wound dressings, implant coatings, and systemic administration. The ultimate goals are infection clearance and tissue healing, although key challenges remain, including long-term toxicity, scalability, and cost. Abbreviations: PEG, polyethylene glycol; FDA, Food and Drug Administration; EMA, European Medicines Agency; GMP, good manufacturing practice; ROS, reactive oxygen species.

4.1. Membrane permeabilization at bacterial interfaces

The bacterial envelope forms a selective barrier. In the wall, teichoic acids in Gram-positive organisms and lipopolysaccharides in the Gram-negative outer membrane contribute to a net negative cell-surface charge; in Gram-negative bacteria, the outer membrane also acts as a permeability barrier that limits the accumulation of many hydrophobic compounds [[43], [44], [45], [46], [47]]. Cationic nanomaterials exploit this electrostatic contrast. The activity and selectivity depend on the surface charge density, hydrophobicity, and nanoscale geometry rather than the charge alone. Hydrophilic polymer-brush silica nanoparticles have a sharp size threshold near 50 nm, where pore-like defects appear in model membranes and bactericidal activity increases while mammalian cytotoxicity remains low [48]. Surface-immobilized antimicrobial peptides on glass trigger membrane depolarization in Staphylococcus aureus within minutes, with ATP leakage and reduced viability evident early, whereas DNA/RNA release occurs later and is peptide dependent [49]. Silver nanoparticles act directly on the plasma membrane of Escherichia coli and Pseudomonas aeruginosa, causing depolarization, potassium efflux, and respiratory inhibition. In combination, silver can potentiate antibiotic activity in vitro and in mouse infection models, including biofilm models [50,51]. Most of these membrane-level observations remain supported primarily by in vitro bacterial assays and selected mouse infection models, and their relevance to complex human infection sites still requires further validation. Two-dimensional carbon provides a complementary physical route: graphene-based sheets can disrupt bacterial envelopes through edge-mediated contact and membrane perturbation, contributing to antibacterial activity in multiple models [52]. Therefore, by balancing the interfacial charge, amphiphilicity, and curvature, nanomaterials can be transformed into highly effective membrane-active agents. Moreover, by increasing antibiotic entry or intracellular retention in bacterial cells, membrane-active nanomaterials can enhance selected combination therapies.

4.2. Bioenergetic control and efflux attenuation

Many clinically relevant multidrug efflux pumps are driven by the proton‒motive force. In these systems, weakening the electrical and chemical gradients slows active export and can increase intracellular drug levels [53]. Nanomaterials can weaken energy-dependent export, downregulate pump expression, or concentrate antibiotics at infected interfaces, thereby increasing intracellular exposure and restoring drug activity against multidrug-resistant bacteria. At the bioenergetic level, silver can enhance aminoglycoside efficacy by bypassing the proton-motive-force–dependent entry step and improving killing in vitro and in mouse models—an effect that has been mechanistically separated from generic oxidative stress [51,54]. Gene-level modulation has also been reported: biosynthesized Fe₃O₄@Ag nanocomposites lower Staphylococcus aureus norA/norB expression and reduce the MIC of ciprofloxacin [55]. Nonmetal systems provide complementary routes. Zinc oxide nanoparticles inhibit efflux in enterococci, as shown by increased Hoechst accumulation and multifold decreases in the MIC [56]. Carbon platforms such as graphene quantum dots show visible-light–activated antibacterial activity through ROS generation and impaired bacterial metabolism; in infected cell models, they can also enhance antibiotic internalization. Graphene oxide provides a complementary route through direct envelope perturbation [57,58]. Delivery formats can also be tuned to improve local action in biofilms and tissues: a near-infrared–triggered nitric oxide hydrogel disperses biofilms and enhances local antimicrobial efficacy through controlled NO release and photothermal activation [59]. Recent gas-mediated strategies further extend this logic: for example, CO-enabled cascade systems can weaken the Gram-negative outer-membrane barrier and enhance the intracellular access of photosensitizers or antibiotics [60]. The S. aureus biofilm-binding DNA aptamer facilitates the accumulation of vancomycin–rifampicin liposomes around biofilm-associated cells and achieves in vitro eradication after 24 h of treatment [61]. Finally, molecularly targeted inhibition of pumps is becoming structurally tractable: Cryo-EM and binding studies on S. aureus NorA have revealed inhibitory antibody fragments that block NorA-mediated efflux and potentiate norfloxacin activity [62]. Together, these threads support a design logic in which nanomaterials attenuate proton-coupled export, interfere with pump function or expression, or increase the local antibiotic concentration at the interface; rigorous evaluation should pair membrane potential or accumulation readouts with MIC or time‒kill shifts in disease-relevant matrices. Thus, membrane-active, ROS-generating, and efflux-modulating strategies should be selected according to infection context because they differ in terms of exposure requirements, host-toxicity windows, and validation readouts.

4.3. Matrix penetration and biofilm remodeling

Because biofilm barriers have been defined above as diffusion, matrix, and metabolic problems, this section focuses on design responses that convert these barriers into actionable nanomaterial strategies. In P. aeruginosa biofilms, the cationic aminoglycoside tobramycin can be sequestered at the biofilm periphery through ionic interactions with the matrix, whereas oxygen limitation and low metabolic activity further reduce killing in interior layers [63,64]. Nanoparticle surface chemistry offers a way through which this barrier can be overcome. Surface functionality can be tuned to balance matrix association with deeper penetration into biofilms. In quantum-dot tracer studies, penetration and distribution depended more on ligand charge and hydrophobicity than on size alone [65].

Concrete designs now couple penetration with active remodeling of the matrix. Mesoporous silica carriers bearing matrix-targeting enzymes such as DNase I, serrapeptase or lysostaphin disperse and kill S. aureus biofilms more effectively than free enzymes do, linking EPS cleavage to biomass loss [66]. Loading DNase I into silver-doped mesoporous silica intensifies dispersal and increases the ability to kill both Gram-positive and Gram-negative biofilms by combining enzymatic breakdown with a local antimicrobial hit [67]. Similarly, programmed EPS degradation combined with photothermal activation has been used to improve penetration and eradicate biofilm wound infections, illustrating the value of coupling matrix loosening with a localized killing modality [68]. Plasmonic alloys add on-demand control in at least some mature biofilm models: under visible light, gold–silver nanoparticles can disturb matrix structure, increase permeability for antibiotic entry, and improve elimination [69]. Graphene–silver composites provide a complementary route by modulating biofilm development and extracellular polymeric substance production while reducing bacterial biomass in P. aeruginosa biofilms [70]. However, the evidence for matrix remodeling remains dominated by in vitro or ex vivo biofilm models, and only a subset of platforms have been tested in chronic wound, implant, or bone infection models.

4.4. Active targeting and molecular interference

Unlike nonspecific membrane disruption or bioenergetic sensitization, active targeting relies on engineered molecular recognition to enrich nanomaterials at bacterial envelopes, biofilm matrices, infected host cells, or defined bacterial targets. Recent species-specific antibacterial material designs further emphasize that pathogen-selective recognition should be considered a core criterion for improving antibacterial precision and reducing nonspecific host exposure [71]. Nanomaterials can be engineered to recognize defined bacterial macromolecules and translate binding into stronger antibacterial effects. One route uses ligand-directed targeting of cell wall motifs: vancomycin-functionalized nanoparticles exploit D-Ala–D-Ala recognition to target Gram-positive cell walls, and when vancomycin is displayed on gold or silver cores, activity against methicillin-resistant S. aureus can increase [[72], [73], [74]]. Beyond antibiotic-derived motifs, targeting peptides and carbohydrate- or polysaccharide-recognizing ligands provide additional routes for bacterial or biofilm localization, particularly when they recognize cell wall components, extracellular polymeric substances, or host-derived matrix proteins enriched at infected interfaces.

The second route relies on nucleic acid addressability: an S. aureus biofilm-binding DNA aptamer facilitates the accumulation of vancomycin–rifampicin liposomes around biofilm-associated cells and achieves in vitro eradication after 24 h of treatment, linking target recognition to local drug exposure in zones that are usually underdosed [61]. Antibody fragments provide another recognition module when structurally defined bacterial proteins are available. For example, inhibitory antibody fragments targeting the S. aureus efflux pump NorA have been shown to block efflux function and potentiate fluoroquinolone activity, illustrating how high-affinity binding elements can be integrated conceptually with nanoscale delivery or surface-presentation strategies to combine target engagement with local antibiotic potentiation.

Sequence-specific molecular interference provides a further layer of active antibacterial design. Peptide–PNA conjugates targeting acyl carrier protein P (acpP) to filament temperature-sensitive mutant Z (ftsZ) or ribonuclease E (rne) inhibit carbapenem-resistant Acinetobacter baumannii at low micromolar concentrations [75]. In E. coli, the uptake of some peptide–PNA conjugates is constrained by the outer-membrane lipopolysaccharide barrier and by inner-membrane transport processes such as SbmA-dependent passage, which guide carrier and linker design [76,77]. Antibiotic–nanoparticle conjugates follow a related logic: nanoscale presentation can increase local ligand density, improve bacterial association, and enhance antibacterial activity relative to the free agent in some systems [78]. Quercetin-coated gold particles and vancomycin-decorated metal nanoparticles further illustrate how surface-presented antibacterial or targeting motifs can improve bacterial interactions [79]. In these strategies, target choice, ligand valency, binding specificity, and nanoscale presentation are the key design levers. Strong studies should pair antibacterial outcomes with direct evidence of target engagement, ligand-dependent localization, sequence-specific activity, enhanced payload accumulation in biofilms or infected tissues, and local pharmacokinetics at the infection site.

4.5. Host-directed immunoregulation

Nanomaterials can fine-tune innate immune responses to speed up pathogen elimination while minimizing tissue damage, complementing their direct antibacterial and antibiofilm effects [80,81]. Macrophage-targeted fusogenic porous silicon nanoparticles that deliver immune-modulating siRNA reprogram alveolar macrophage responses and improve survival in bacterial pneumonia [82]. Peptide-coated gold nanoparticles shift macrophage programs toward resolution and protection against acute lung injury in vivo [83]. Trained-immunity concepts are now feasible with materials, as β-glucan–coupled superparamagnetic iron oxide nanoparticles increase phagocytosis and confer protection against sepsis and secondary infection [84]. Local immunoregulation can be layered onto antibiofilm therapy: a near-infrared–responsive nitric oxide hydrogel disperses chronic biofilms, promotes wound closure and regulates local inflammation [59]. Because opsonins, complement activation and the protein corona shape nanoparticle fate and inflammatory tone, designs that manage these interactions are desirable [85].

The host immune response is not only a downstream consequence of bacterial killing but also a determinant of therapeutic outcome. Nanomaterials may promote bacterial clearance by enhancing macrophage phagocytosis, reprogramming macrophage polarization, regulating neutrophil recruitment, modulating complement activation, or influencing neutrophil extracellular trap formation. However, excessive immune activation can aggravate tissue injury, especially in pneumonia, sepsis, chronic wounds, and implant-associated infection. Therefore, host-directed antibacterial nanomaterials should be evaluated using both microbiological endpoints and immune injury readouts, including cytokine profiles, immune cell infiltration, complement activation, oxidative tissue damage, and repair markers.

5. Classes of nanomaterials in antibacterial applications

Antibacterial nanomaterials can also be viewed from a material-class perspective because each platform family offers a distinct combination of physicochemical activity, formulation flexibility, tissue compatibility, and translational constraints. The following sections summarize representative material classes according to their class-specific strengths, preferred infection scenarios, and major development barriers [86,87]. To align the scope of the Review with the infection-cascade framework, we discuss four representative platform categories: metal nanoparticles and metal nanocomposites, carbon-based platforms, polymeric and lipid-compatible organic carriers and programmable biomacromolecular or self-assembled systems with options for responsive integration. Across classes, shared advantages include access to bacterial envelopes, biofilm matrices and infection-specific microenvironments, which can impose multisite pressure and reduce reliance on a single molecular target. The subsections sketch the core design logic and where each class is most useful. To facilitate cross-class comparisons, representative experimental evidence and key functional outcomes across these major nanomaterial classes are summarized in Fig. 3.

Fig. 3.

Representative experimental evidence across major nanomaterial classes for antibiotic-resistant infections.

This figure summarizes class-specific antibacterial nanomaterial strategies by linking representative design principles, typical experimental evidence, and key functional or translational outcomes. Metal and metal oxide nanomaterials act through ion release, reactive oxygen species (ROS) generation, catalytic antibacterial activity, local drug reservoir effects, and photothermal or photocatalytic activation. Representative evidence includes (a) scanning electron microscopy (SEM) showing bacterial membrane disruption after silver nanoparticle treatment [88] and (b) confocal laser scanning microscopy (CLSM) and in vivo imaging/quantification showing disruption of mature S. aureus biofilms and reduced bacterial burden after AgNP hydrogel treatment. Carbon-based nanomaterials, including graphene oxide (GO), graphene quantum dots (GQDs), GO–Ag composites, and carbon nanogels, can undergo physical cutting or wrapping, edge-mediated membrane damage, light-responsive ROS generation, membrane-potential dissipation, and biofilm interference [89]. Representative evidence includes (c) live/dead biofilm viability analysis after GO-based treatment [90]. (d) biological transmission electron microscopy (Bio-TEM) showing nanomaterial-induced membrane deformation and ultrastructural injury [91], and (e) serial-passage assays showing constrained resistance evolution after carbon nanogel exposure. Polymeric and lipid nanomaterials, including liposomes, fusogenic liposomes, polymeric nanoparticles, hydrogels, nanogels, and stimuli-responsive carriers, mainly improve local antibiotic exposure, controlled release, bacterial or biofilm association, and tissue compatibility [92]. Representative evidence includes (f) liposome morphology and in vitro drug release profiles [93] and (g) a MRSA-infected wound model showing improved wound repair and antibacterial efficacy after polymeric nanoparticle treatment. Biomacromolecular and self-assembled platforms, including DNA origami, tetrahedral framework nucleic acids, aptamer-guided constructs, peptide assemblies, and natural-product coassemblies, offer programmable targeting, multivalent displays, sequence addressability, carrier-free self-assembly, and high payload density [94]. Representative evidence includes (h) tetrahedral framework nucleic acid–ampicillin delivery against MRSA [95] and (i) DNA origami-based antimicrobial delivery, illustrating bacterial targeting, enhanced local accumulation, and improved antibacterial efficacy relative to free cargo [96]. Collectively, these examples show that material selection should be matched to the infection context and validated using complementary readouts, including membrane damage, biofilm disruption, bacterial burden reduction, resistance-passage testing, controlled release, and in vivo infection models. Abbreviations: AgNPs, silver nanoparticles; MSN@Ag, silver-containing mesoporous silica nanoparticles; Au–Ag, gold–silver nanomaterials; ZnO/CuO, zinc oxide/copper oxide; MOFs, metal–organic frameworks; GO, graphene oxide; GQDs, graphene quantum dots; NPs, nanoparticles; ROS, reactive oxygen species; SEM, scanning electron microscopy; CLSM, confocal laser scanning microscopy; Bio-TEM, biological transmission electron microscopy; MRSA, methicillin-resistant S. aureus; tFNAs, tetrahedral framework nucleic acids.

5.1. Metal nanoparticles and metal nanocomposites

Metal nanoparticles and metal nanocomposites are among the most mature antibacterial platforms because they combine broad multisite activity, strong interfacial reactivity, and compatibility with coatings, porous reservoirs, wound dressings, and device-adjacent formats. Their class-specific value lies in the ability to concentrate physicochemical pressure at infected interfaces, especially in surface-associated biofilms, wounds, implants, and locally accessible infection sites where conventional antibiotics often fail to maintain sufficient exposure. Representative systems include silver-, zinc-, copper-, titanium-, magnetite-, and MOF-based hybrids, which can be adapted for local release, surface protection, or externally assisted activation [97,98]. Copper-based nanomaterials can induce bacterial injury through copper release, redox imbalance, membrane damage and proteotoxic stress; some recent studies have described related phenotypes as cuproptosis-like, but this terminology should be used cautiously because bacterial copper-dependent injury remains mechanistically distinct from canonical eukaryotic cuproptosis [99]. Representative designs show how this translates into an outcome. A mesoporous silica carrier with a silver core and levofloxacin in the pores produced clear synergy in vitro and reduced the Escherichia coli burden by approximately three logs in a mouse peritonitis model, illustrating how a local reservoir lifts drug levels at the lesion [100]. Metal nanocomposites expand the mechanism set and add durability: Ag–TiO₂ coatings combine silver chemistry with photocatalysis and show strong antibacterial activity on titanium substrates, with biocompatibility depending on the formulation and coating conditions; ZnO–CuO and related mixed-oxide systems exhibit broad antibacterial activity and can be tuned for improved biocompatibility through polymer capping [[101], [102], [103]]. MOF-based hybrids extend metal platforms into soft tissue: two-dimensional MOF carriers loaded with glucose oxidase self-activate in glucose-containing wound settings and promote antibacterial wound healing in vivo [104]; in infected diabetic wounds, ZIF-8 carriers coloaded with glucose oxidase and ciprofloxacin enhance local antibacterial performance and promote healing [105]. Recent implant-oriented hybrid systems, including ZIF-based responsive interfaces, further extend this logic by integrating antibacterial activity, localized release, and osteoimmunomodulation for device-associated infection control [106,107]. The conjugation of magnetite with vancomycin adds a capture function that binds bacterial cell walls, promotes magnetic separation, and suppresses growth [108]. In practice, these platforms have three advantages for resistant infections and biofilm disease: broad multisite pressure that may be more difficult to evade than single-target strategies; tools for concentrating action where bacteria reside; and compatible formats for coatings, dressings and device-adjacent therapy. However, the same ion release and redox reactivity that support antibacterial potency also create translational constraints, including persistent metal accumulation, uncontrolled oxidative flux, protein-dependent changes in surface reactivity, and batch-to-batch variability. Catalytic output must therefore be tuned within a therapeutic window that balances bactericidal intensity against host oxidative tolerance. Future metal-based systems should report ion release profiles under infection-relevant pH and protein conditions, dose-dependent host-cell toxicity, hemocompatibility, tissue retention, and clearance routes rather than relying only on nominal particle concentration or short-term MIC values.

5.2. Carbon-based nanomaterials

Carbon-based nanomaterials are distinguished by their geometry-dependent interactions with bacterial cells and biofilm structures. Graphene sheets, graphene oxide, carbon nanotubes, carbon dots, and related two-dimensional materials provide sharp edges, high surface areas, tunable oxidation states, and large loading interfaces, allowing them to serve as contact-active, cargo-bearing, or externally activated antibacterial platforms. These features make carbon-based systems particularly relevant for surface-associated infections, wound biofilms, and anatomically accessible sites where local activation by light, heat, or ultrasound is feasible [[109], [110], [111]]. In chronic-wound-related isolates, graphene oxide reduces biofilm mass and disrupts three-dimensional structure; in cell models, higher doses can also reduce intracellular S. aureus survival, extending activity beyond the extracellular matrix [112,113]. Graphene quantum dots add a light-addressable option: under visible light, they generate reactive oxygen species and kill methicillin-resistant S. aureus and E. coli. [57]. Composite designs have a wide range of effects; graphene oxide–silver hybrids modulate extracellular polymeric substance production and biofilm development, and related wound-dressing formats have shown antibacterial activity with healing benefits in preclinical models [70,114]. In addition to graphenic sheets, two-dimensional sulfides add catalytic and externally addressable killing in hydrated tissues; MoS2-based nanozyme hydrogels have shown antibacterial activity and promote infected-wound closure; PEG-modified MoS2 nanoflakes enable strong near-infrared photothermal killing; and ultrasound-switchable nanozyme systems generate reactive species during ultrasound activation to clear multidrug-resistant infections with reduced off-target exposure [[115], [116], [117], [118], [119]]. A newer line uses carbon nanogels that combine membrane potential dissipation with oxidative damage; their minimum inhibitory concentrations remain almost unchanged after twenty serial passages, whereas those of silver nanoparticles and small-molecule comparators increase markedly, suggesting slower resistance evolution under multisite pressure. [92]. Despite these advantages, carbon-based systems remain limited by unresolved issues in translational safety and exposure control. Antibacterial performance depends strongly on lateral size, aspect ratio, defect density, oxidation state, and aggregation behavior, making cross-study comparisons difficult and complicating quality control. Some graphenic and tubular materials may persist in tissues, trigger inflammatory priming, or exhibit dose-dependent cytotoxicity and hemocompatibility issues, especially when surface chemistry is not tightly controlled. In terms of photo- or ultrasound-activated designs, efficacy may also depend on penetration depth, energy delivery, and device compatibility, which can restrict use in deep or anatomically complex infections. For carbon-based materials, translational evaluation should therefore connect degradability, tissue persistence, clearance route, inflammatory priming, hemocompatibility, and repeated-dose safety with the antibacterial exposure required in each infection model.

5.3. Polymeric and organic nanomaterials

Polymeric, lipid-compatible, and other organic nanomaterials are characterized by flexibility, biodegradability, tunable surface chemistry, and controlled-release capacity. Compared with persistent inorganic or graphenic platforms, many organic carriers offer clearer degradation routes and greater adaptability for local depots, liposomes, micelles, hydrogels, nanogels, and layer-by-layer assemblies. Their main goal is to improve the therapeutic index of antibacterial treatment by protecting payloads, prolonging local exposure, enabling infection-responsive release, and reducing unnecessary systemic exposure. Star-shaped peptide polymers built from lysine–valine arms rapidly disrupt gram-negative membranes and suppress growth in mouse infection models, with a high apparent barrier to resistance in repeated-exposure studies [120]. Biodegradable guanidinium-functionalized polycarbonates provide a related, fully synthetic option, with activity against multidrug-resistant Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, E. coli, and MRSA in murine models, without detectable resistance after repeated exposure and with low toxicity at active doses [121]. Soft carriers further increase local antibiotic exposure and help drugs reach protected niches. Fusogenic liposomes encapsulating vancomycin show enhanced activity against mature S. aureus biofilms and improve killing [93], and local codelivery formats, such as DNase I plus liposomal vancomycin in a thermosensitive hydrogel, eradicate bacteria on bone and implant surfaces and restore fracture healing in rats [122]. In addition to liposomes, charge-reversing layer-by-layer particles that switch to cationic states in acidic biofilm microenvironments increase retention and payload delivery, and ROS-responsive hydrogels time the release of antibacterial and anti-inflammatory agents to the wound milieu, accelerating wound closure and repair in MRSA-infected skin [[123], [124], [125]]. Related wound-oriented hydrogels are being designed to integrate infection control with metabolic regulation and tissue repair, as illustrated by dihydromyricetin-loaded systems for diabetic wound healing and glycemic control [126]. Within this class, nanogels and hydrogel-derived nanoparticles offer mesh-controlled loading and release, adhere to hydrated matrices, and can codeliver antibiotics with enzymes or photothermal agents across wound, bone, and device-associated infection settings [127]. Compared with some nondegradable carbon allotropes, many polymeric carriers offer clearer biodegradation pathways. For polymeric and lipid-compatible carriers, translational uncertainty remains linked to degradation products, repeat-dose tolerability, complement activation-related pseudoallergy, sterilization stability, batch reproducibility, long-term biodistribution, and clearance kinetics.

5.4. Programmable biomacromolecular and self-assembled platforms

5.4.1. DNA nanostructures

Programmable biomacromolecular and self-assembled platforms add spatial and molecular precision to antibacterial material design. DNA nanostructures, aptamer-guided assemblies, peptide-based systems, and natural-product coassemblies can organize antibacterial motifs with defined valency, spacing, orientation, and payload density. Their advantages include programmability, multivalent presentation, target recognition, and carrier-free or minimal-carrier assembly, making them particularly useful when antibacterial efficacy depends on precise localization or high local payload density [128]. Tetrahedral frameworks and origami sheets can display enzymes, peptides or ligands with nanometer-level control and preserve activity after conjugation; lysozyme presented on DNA origami suppresses bacterial growth more effectively than the free enzyme does, while compact DNA tetrahedra likewise enhance lysozyme activity against MRSA and E. coli [95,96,120]. Nucleic acid recognition can localize payloads at the site of infection. Species-specific DNA aptamers guide DNA-scaffolded silver nanoclusters to Pseudomonas aeruginosa, rapidly depolarizing bacterial cells and improving survival in a Galleria mellonella infection model [129]. Work from Lin Yunfeng's team showed that tetrahedral DNA can carry antisense peptide nucleic acids against ftsZ into MRSA and suppress gene expression with concentration-dependent growth inhibition; in related studies, tetrahedral DNA loaded with ampicillin increases bacterial uptake, increases MRSA susceptibility, and decreases resistance development relative to the free drug [130,131].

5.4.2. Peptide and natural-product self-assembly

Carrier-free or minimal carrier self-assembly results in a high payload density with simple composition. Intelligent peptide-based nanomaterials provide a related programmable route by combining self-assembly, targeting, stimuli responsiveness, and infection-microenvironment-triggered structural transformation [132]. Coassembled alkaloids and polyphenols, such as berberine with rhein, form stable particles that improve aqueous stability and antibacterial activity over the free constituents [133]. Recent infection-responsive polyphenol-based nanoassemblies further extend this strategy by integrating antibacterial payloads with microenvironment-triggered activation and inflammation control [134,135]. Hybrid natural-product constructs can integrate inorganic elements: epigallocatechin gallate coats silver nanoparticles that self-assemble with selenium nanowires to disrupt biofilms, increase reactive oxygen species, and promote healing in infected wounds with negligible in vivo toxicity [136]. Dynamic supramolecular dendrimers provide potent activity against drug-resistant bacteria and biofilms through multivalent membrane engagement and membrane-lytic action [137]. Size-transformable chimeric peptide assemblies switch from fibers to nanoparticles in acidic biofilm environments, penetrate biofilms more effectively and reduce bacterial load in animal models [132]. Representative examples across priority pathogens are summarized in Table 2. These features make biomacromolecular and self-assembled platforms particularly attractive for chronic and biofilm-associated infections where programmable targeting, high local payload density and tissue compatibility are important. Because direct cross-study ranking is confounded by differences in bacterial strains, media, infection matrices, dosing routes, and endpoints, future reports should use a minimum shared metric set, including MIC or MBEC shift, log10 CFU reduction, time-kill kinetics, host-cell toxicity, intracellular bacterial clearance where relevant, and lesion-level pharmacokinetics.

Table 2.

Representative nanomaterials against priority antibiotic-resistant pathogens.

Representative material/system	Mechanistic highlights	Representative pathogen/model organism	Model	Key outcome
Metal nanoparticles and metal nanocomposites
Ag@MSNs@LEVO [100]	Silver core plus levofloxacin produces synergistic killing, local drug reservoir raises exposure at the lesion.	E. coli	Mouse acute peritonitis	Nearly three orders of magnitude reduction in bacterial burden in a mouse acute peritonitis model.
Ag/TiO2	Silver chemistry plus photocatalysis on implant surfaces.	S. aureus, E. coli	In vitro on Ti substrates	Strong antibacterial activity on Ti substrates; biocompatibility depends on coating composition and preparation conditions.
PEG–(ZnO/CuO) NCs [103]	Broad bactericidal activity, tunable by composition, option for light assistance.	S. aureus, E. coli	In vitro	Potent antibacterial with low cytotoxicity
CIP/GOx@ZIF-8 [105]	Enzyme generates H2O2in situ, co-delivered antibiotic enhances kill, diabetic-wound model.	MRSA	Diabetic wound in rats/mice	Improved closure and bacterial clearance vs single agents
Fe3O4/DOPA/Van [108]	Vancomycin-mediated cell-wall capture and magnetic separation with growth suppression.	MRSA, other Gram-positive	In vitro	Concentration-dependent growth suppression; magnetic preconcentration of Gram-positive bacteria.
Carbon-Based Materials
Graphene oxide [112]	Mechanically and chemically disrupts biofilms, can affect intracellular S. aureus in cell models	S. aureus, P. aeruginosa	In vitro biofilms, cell infection models	Biofilm mass reduction; reduced intracellular S. aureus survival at higher dose.
Graphene quantum dots (GQDs) [57]	Visible-light ROS generation and impaired bacterial metabolism.	MRSA, E. coli	In vitro, infected-cell models	Light-activated killing; enhanced antibiotic internalization/potentiation in infected-cell models.
GO-AgNPs [70]	Modulates EPS production and biofilm development.	P. aeruginosa	In vitro biofilm	Reduced biomass in mature P. aeruginosa biofilms.
Carbon nanogels (CNGs) [92]	Membrane-potential dissipation, oxidative damage	S. aureus, E. coli	In vitro	MIC remained almost unchanged after 20 passages.
Polymeric & Organic Systems
SNAPPs [120]	Outer-membrane disruption, membrane destabilization, multitarget killing.	Colistin-resistant A. baumannii	In vitro, in vivo	Rapid antibacterial activity with a high apparent barrier to resistance.
Guanidinium-functionalized polycarbonates [121]	Selective membrane activity with low hemolysis via amphiphilic balance	MRSA, E. coli	In vitro, mouse wound model	Potent antibacterial activity with low toxicity at active doses; no detectable resistance after repeated exposure.
VAN-niosome [138]	Sustained release and improved biofilm eradication compared with free vancomycin, with altered expression of the biofilm-associated regulatory gene icaR	Clinical MRSA isolates	In vitro biofilm assays	MBEC reduced vs free vancomycin
LUVfusoVAN [93]	Membrane fusion increases penetration into mature biofilms	MRSA	In vitro biofilms, in vivo	Enhanced anti-biofilm activity vs non-fusogenic liposomes
Biomacromolecule & self-assembly
DNA origami carrying lysozyme [95]	Multivalent enzyme display preserves activity after conjugation.	E. coli	In vitro	Stronger growth inhibition than free lysozyme.
tFNAs-Ery [139]	Enhances bacterial uptake and membrane permeabilization, boosts erythromycin activity	E. coli	In vitro	Greater antibacterial effect vs free erythromycin, improved intracellular delivery
Berberine–rhein co-assembled nanoparticles [133]	Carrier-free particles of natural products, improved stability and potency.	MRSA, E. coli	In vitro, in vivo	Enhanced antibacterial efficacy vs free compounds

Note: LUVfusoVAN, fusogenic large unilamellar vancomycin-loaded vesicles.

Antibacterial potency must be balanced against host compatibility when nanomaterial platforms for translation are being assessed. This balance is especially important for cationic materials, whose affinity for negatively charged bacterial envelopes and biofilm matrices can improve retention and antibiotic uptake but may also increase hemolysis, mammalian membrane perturbation, complement activation, or inflammatory injury. Infection-responsive systems, such as pH-responsive polymers, charge-reversal carriers, enzyme-responsive platforms, ROS-responsive hydrogels, and biodegradable lipid-compatible formulations, may provide better selectivity by concentrating activity within acidic, protease-rich, or oxidative infection microenvironments. Future comparisons should therefore report not only MIC reduction, biofilm eradication, or log-kill efficacy but also host-cell toxicity, hemocompatibility, inflammatory injury, and tissue-level safety in disease-relevant models.

6. Nanomaterial–antibiotic synergy and theranostic integration

Building on the preceding discussion of material classes, this section further examines how nanomaterials can be integrated with conventional antibiotics and diagnostic functions to translate their mechanistic advantages into exposure-guided and response-adapted therapeutic strategies. An integrated overview of this framework is provided in Fig. 4, highlighting nanomaterial–antibiotic pharmacodynamic synergy, nanodiagnostic susceptibility profiling, and imaging-guided or externally triggered therapeutic modalities.

Fig. 4.

| Nanomaterial–antibiotic synergy and theranostic integration. This schematic summarizes the conceptual framework of Section 6, covering pharmacodynamic synergy, nanodiagnostics, rapid susceptibility profiling, imaging-guided activation, and response monitoring. Pharmacodynamic synergy and resistance containment are illustrated through four major mechanisms: membrane permeabilization, which increases antibiotic entry; efflux attenuation, which reduces drug export; nanocarrier-mediated drug protection from degradative enzymes; and local depot or triggered release, which promotes biofilm penetration and site-specific exposure. These mechanisms are linked to key evidence standards for synergy, including a fractional inhibitory concentration index (FICI) ≤ 0.5, ≥2×log10 colony-forming unit (CFU) reduction relative to the most active monotherapy, a reduced minimum biofilm inhibitory concentration (MBIC) or minimum biofilm eradication concentration (MBEC), and slower minimum inhibitory concentration (MIC) drift during serial passaging. Nanodiagnostics and rapid susceptibility profiling integrate pathogen capture, molecular or metabolic readouts, rapid antimicrobial susceptibility testing (AST), and treatment decision-making to support optimized or alternative therapy. Imaging-guided and externally triggered modalities enable the localization of infection by fluorescence, photoacoustic imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), or single-photon emission computed tomography (SPECT), followed by externally triggered activation using near-infrared (NIR) light, ultrasound, or magnetic fields. Monitoring the resulting response can track reduced bacterial burden, biofilm disruption, and tissue recovery, supporting spatially and temporally controlled antibacterial therapy. Abbreviations: AST, antimicrobial susceptibility testing; CFU, colony-forming unit; FICI, fractional inhibitory concentration index; MBEC, minimum biofilm eradication concentration; MBIC, minimum biofilm inhibitory concentration; MIC, minimum inhibitory concentration; MRI, magnetic resonance imaging; NIR, near-infrared; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

6.1. Pharmacodynamic synergy and resistance containment

Nanomaterials potentiate legacy antibiotics through four convergent routes. Transient permeabilization of bacterial envelopes can increase uptake across Gram-negative and Gram-positive barriers and may partly compensate for reduced permeability caused by porin loss or outer-membrane crosslinking. Attenuation of the proton‒motive force can diminish the activity of proton-coupled efflux systems and prolong the intracellular residence of codelivered drugs [140]. Steric protection or sacrificial chemistries can preserve active drug fractions in the presence of β-lactamases and drug-modifying enzymes. Control of local pharmacokinetics at infected interfaces—via depots, mucoadhesive formulations and stimuli-responsive release—sustains therapeutically relevant concentrations within biofilms, abscesses and hypoperfused tissues. Gas therapy, including NO-, CO-, H₂S-, O₂-, and H₂-based strategies, provides another exposure-controlled combination route by coupling antibacterial activity with biofilm disruption, immune modulation, or tissue repair, although dose, release kinetics, tissue penetration, and gas-related toxicity remain key constraints [141]. In anatomically confined infections, such as endodontic biofilms, nitric oxide release combined with photodynamic activation has also been adapted into local irrigation platforms, supporting the broader principle that antimicrobial synergy should be assessed together with tissue compatibility and postinfection repair [142].

Claims of synergy require orthogonal and prespecified criteria, ideally demonstrated in the same disease-relevant matrix. Multifunctionality alone should therefore be described as enabling or complementary unless the combined platform exceeds the most active single component according to predefined synergy criteria. A defensible synergy package should include at least two orthogonal readouts, preferably measured in the same disease-relevant matrix: a commonly accepted checkerboard criterion such as a fractional inhibitory concentration index ≤0.5; a reduction in minimal biofilm inhibitory or eradication concentrations relative to each agent alone; or a ≥2×log10 decrease in CFU/mL for the combination relative to the most active single agent in time–kill assays. Supporting evidence may include increased intracellular antibiotic accumulation measured by quantitative mass spectrometry or calibrated imaging and reduced frequencies of resistance emergence during serial passaging [143,144]. Framing synergy and mechanisms in this way creates an auditable design space for cross-platform comparison. A practical checklist of mechanistic modules and quantitative heuristics is provided in Box 2. Resistance containment is a plausible but still undertested rationale for nanomaterial–antibiotic combinations. Nanomaterials may slow resistance emergence by dispersing antimicrobial pressure across multiple bacterial targets, enhancing antibiotic uptake, weakening proton-coupled efflux, and sustaining local drug levels above the mutation selection window. However, the current evidence is uneven, as few studies have included serial passaging, mutant prevention concentration assays, or postexposure genomic analyses. Future work should therefore report longitudinal MIC shifts, resistance frequency, postwithdrawal regrowth, and genomic or transcriptomic adaptation after repeated nanomaterial exposure, especially in disease-relevant media and biofilm models.

Box 2 | Key criteria for evaluating nanomaterial–antibiotic synergy.

Mechanistic modules
Permeabilize membranes. Cationic or amphiphilic interfaces transiently disorder the Gram-negative outer membrane and the gram-positive cytoplasmic membrane, thereby increasing uptake of hydrophilic drugs. Disrupt the proton motive force and attenuate efflux. Interactions with membrane lipids or respiratory enzymes reduce ΔΨ and ΔpH, diminishing RND and MFS pump activity and prolonging intracellular residence of partner antibiotics. Shield degradative enzymes. Encapsulation and steric shells limit access of β-lactamases and aminoglycoside-modifying enzymes, while sacrificial or decoy linkers preserve the active drug fraction. Provide depot pharmacokinetics. Adhesive carriers and hydrogels can localize and sustain antibiotic exposure at infected interfaces under endogenous or externally applied triggers.
Design levers
Charge and multivalency. Tune surface charge density and ligand valency to maximize bacterial association and, where relevant, intracellular drug accumulation within hemocompatible limits. Size and matrix affinity. Select suitably small particles with tuned surface functionality and balanced affinity for EPS to penetrate biofilms while minimizing peripheral trapping. Linkers and triggers. Match release kinetics to antibiotic half-life and to cues present at the site, including acidic pH, bacterial or host enzymes and oxidative stress; consider light, ultrasound or magnetic inputs only when feasible in vivo. Scaffold selection. Prioritize metal or carbon frameworks when membrane-active or catalytic mechanisms are desired; prefer polymer or lipid scaffolds when depot formation, soft-tissue compatibility or blood compatibility are priorities. Targeting ligands. Deploy pathogen or matrix-recognizing moieties to bias localization without compromising safety.
Evidence standards for calling synergy
Supportive evidence: Decreases in MIC or MBC for the antibiotic in combination relative to the corresponding monotherapy. Increased intracellular antibiotic accumulation quantified by LC–MS/MS or calibrated fluorescence imaging. Lower frequency of resistance emergence during serial passage or a downward shift in mutant prevention concentration. Core synergy criterion: Checkerboard FICI ≤0.5 with transparent calculation. Reductions in MBIC and/or MBEC with device, endpoint and exposure times clearly stated. A ≥2×log10 CFU/mL decrease for the combination relative to the most active single agent in time–kill assays, with regrowth assessed over prespecified intervals. Assay caution: Nanoparticles may interfere with MIC or viability assays through light scattering, intrinsic absorbance, sedimentation, dye adsorption, or medium turbidity. OD-based results should therefore be confirmed using CFU enumeration, orthogonal viability assays, calibrated imaging, or drug-accumulation measurements with particle-only controls.

6.2. Nanodiagnostics and rapid susceptibility profiling

Nanoscale transducers expand the diagnostic armamentarium for culture-independent pathogen identification and early susceptibility assessment. Surface-enhanced Raman spectroscopy (SERS) on plasmonic gold or silver substrates can amplify bacterial Raman fingerprints and, when coupled with antibody-, aptamer-, or lectin-mediated capture, improve the detection of low-abundance pathogens in blood, urine, wound exudates, or respiratory samples [144,145]. Importantly, SERS-based readouts may also capture early metabolic changes after antibiotic exposure, providing a potential route toward rapid phenotypic susceptibility assessment. Nanostructured electrochemical sensors based on gold nanoparticles, graphene derivatives, magnetic nanoparticles, or metal–organic frameworks can detect resistance genes, β-lactamase activity, virulence factors, bacterial metabolites, or nucleic acid targets with high analytical sensitivity. Label-free plasmonic systems, including surface plasmon resonance, may further support real-time analysis of bacterial binding and ligand-mediated capture, although their clinical utility for susceptibility profiling remains less established.

Analytical performance must ultimately be linked to clinical decision timelines. Workflows that integrate on-chip concentration, selective capture, single-cell metabolic reporters, and rapid antibiotic-response readouts can shorten susceptibility testing toward clinically actionable timeframes [146]. Embedding these diagnostic functions within theranostic constructs may also enable parallel monitoring of localization, delivery, and treatment response, thereby informing treatment adjustment when source control is uncertain or when the biofilm burden is high [147].

6.3. Imaging-guided and externally triggered modalities

Imaging-addressable nanomaterials integrate lesion localization, biodistribution monitoring, and therapeutic activation. Near-infrared absorbers enable photoacoustic mapping and photothermal treatment; superparamagnetic cores provide MRI contrast and may support magnetic targeting, and radiometal-labeled constructs allow PET or SPECT tracking of systemic biodistribution and lesion accumulation [148]. Photoacoustic imaging-guided photothermal systems are particularly attractive for superficial, wound-associated, or surgically accessible infections, where lesion localization, accumulation monitoring, and externally controlled bacterial killing can be coordinated with local procedures such as debridement when clinically feasible [149].

Externally triggered systems add spatiotemporal precision. Compared with purely light-triggered platforms, magnetic and ultrasound-responsive materials may offer better access to deeper or implant-associated infections, although the actuator dose, tissue heating, cavitation safety, and device compatibility must be reported in a standardized manner. Photothermal and photodynamic constructs can disrupt biofilm matrices and increase the susceptibility of sessile bacteria to coadministered antibiotics, whereas sonodynamic and magnetothermal strategies may extend activation to deeper tissues and implant-associated settings [150]. Cascade designs that require both endogenous infection cues, such as acidity, proteases, or bacterial toxins, and external inputs may restrict activity to infection foci and help limit collateral injury [151]. Best-practice reporting should specify actuator parameters, tissue-safe operating margins, orthogonal confirmation of localization, and microbiological endpoints [152].

7. Nanomaterial properties and design principles in antibacterial applications

The antibacterial performance of nanomaterials reflects a coordinated set of physicochemical levers rather than the composition alone, and these same levers ultimately shape translational feasibility (Fig. 2B). Particle size influences where catalysis and drug exposure occur: ultrasmall constructs can access dense cell-envelope architectures more effectively and place reactive centers closer to vulnerable compartments, whereas larger particles more often behave as interfacial depots that sustain concentrations at biofilm surfaces and in poorly perfused tissue planes [[153], [154], [155], [156]]. Morphology amplifies this spatial control; edge-rich two-dimensional sheets such as graphene oxide and MXenes can wrap, shear, or puncture envelopes, whereas rod- and sheet-like shapes may promote more disruptive contact than spheres, which often rely more on adsorption and ion- or ROS-mediated effects [157,158].

Surface chemistry governs selectivity and stability: pathogen- or matrix-recognizing ligands can bias localization to biofilms or bacterial interfaces [159]; polymeric or zwitterionic shells help maintain colloidal integrity in protein-rich inflammatory fluids and tune penetration through extracellular polymeric substances [160]; and antifouling surface designs can modulate opsonization, complement engagement and protein-corona evolution [161]. Responsiveness provides temporal gating: acidic pH, oxidative burden, or bacterial enzymes trigger release in situ, whereas external inputs—light, magnetic fields, or acoustic energy—superimpose photothermal or photodynamic reactions and mechanical disruption for spatiotemporally controlled activation [[162], [163], [164], [165], [166], [167]]. Hybrid architectures integrate these functions within a single chassis. For example, MXene–polymer composites can couple photothermal conversion with biofilm disruption, thereby accelerating bactericidal kinetics without increasing the systemic dose [168,169].

From a translational perspective, these physicochemical parameters directly shape the pharmacokinetics, safety, and feasibility of repeated doses. Biodegradable lipids, polymers, dendrimeric assemblies, and peptide-based systems may support repeated administration through clearer degradation routes [170], whereas persistent inorganic platforms require defined elimination pathways, long-term retention assessment, and tissue-level safety evaluation [171]. Protein corona formation is another critical determinant of in vivo performance. In serum, wound exudates, sputum, or inflammatory tissue fluids, nanoparticles rapidly adsorb proteins, lipids, complement factors, and extracellular matrix fragments, which may mask cationic or targeting ligands, reduce bacterial binding, alter biofilm penetration, redirect macrophage or neutrophil uptake, activate complement, and change biodistribution or clearance. Therefore, antibacterial activity measured in simple culture media should be validated in protein-rich and disease-relevant matrices before being used to support translational claims. Effective antibacterial nanomaterials should therefore integrate size, shape, and surface chemistry and trigger modules to generate high local activity at pathogen–matrix interfaces, sustain multitarget pressure that may reduce resistance risk, and minimize host injury. In this framework, composition is only one component of a tunable design system that links mechanism, exposure, safety, and clinical positioning [172]. A concise, practice-oriented checklist is summarized in Box 3.

Box 3 | Key considerations for nanomaterials.

Size ·Ultrasmall regimes: High curvature and large surface-to-volume ratio increase catalytic site density and facilitate access across dense cell-wall architectures, often amplifying ROS generation and membrane interaction. ·Biofilm penetration: Suitably small particles with tuned surface functionality can diffuse into biofilm voids and reach embedded subpopulations, with pore size and diffusivity strongly dependent on species and biofilm maturity.

Surface chemistry ·Charge-dependent interactions: Cationic surfaces enhance binding to anionic envelopes (teichoic acids, LPS), but optimal charge density is required to balance bacterial affinity with host-cell compatibility and protein corona formation. ·Stimuli-responsive coatings: pH-, ROS-, or enzyme-triggered shells enable on-site activation and dose sparing at infection loci. ·Biomolecular ligands: Peptides, polysaccharides, antibodies or antibiotic motifs can bias localization to S. aureus biofilms or Gram-negative interfaces and, in some systems, improve penetration through EPS. ·Protein corona control: PEG, zwitterionic coatings, biomimetic membranes, albumin precoating, or deliberately preformed coronas can be used to stabilize colloids, reduce nonspecific opsonization, and preserve targeting or antibacterial activity in protein-rich fluids.

Shape/morphology ·Facet/edge-rich architectures: Nanoplates and sheets with sharp edges and high facet density may promote membrane disruption relative to more isotropic shapes. ·Aspect ratio effects: Rod-like and sheet-like morphologies may increase contact time and the probability of piercing or wrapping within matrices. ·2D nanostructures: Vertically oriented graphene- or MXene-like sheets leverage edge effects for physical envelope damage and biofilm disruption.

Responsiveness & external control ·Infection-site cues can trigger release, while light, magnetic fields or acoustic energy provide noninvasive external control over photothermal, photodynamic or mechanical disruption when penetration depth and device access are adequate.

Biodegradability & safety ·Degradable carriers (lipid, polymer, peptide assemblies) facilitate clearance and repeat dosing; persistent inorganics warrant defined elimination routes and long-term retention/toxicity evaluation prior to translation.

8. Applications in preclinical and clinical infection models

To evaluate whether the proposed modules are biologically meaningful, this section maps nanomaterial strategies onto preclinical and clinical infection models that represent planktonic, intracellular, biofilm-associated, and relapse-prone disease contexts. Building on these design principles, research on antimicrobial nanomaterials for multidrug-resistant planktonic and biofilm infections has expanded rapidly, yet the evidence base remains weighted toward in vitro studies, with fewer investigations advancing to animal models and fewer to human evaluation. Moreover, heterogeneity in infection models, dosing paradigms, and microbiological endpoints complicates cross-study comparisons, and the predictive value of small-animal models for human pharmacokinetics and tissue penetration remains limited [173]. Progress therefore depends on indication-matched in vitro and in vivo models that demonstrate both efficacy and safety, together with more standardized biocompatibility and nanotoxicology frameworks, careful control of nanospecific assay interference and artifacts, and tight control of critical quality attributes across batches [174,175]. Here, we connect tunable physicochemical parameters to antibacterial mechanisms; organize the evidence across planktonic, intracellular, and biofilm infections; and end with a critical assessment of clinical progress and what is needed for translation (Fig. 2C).

8.1. Planktonic infections

Planktonic bacteria represent the earliest and most accessible stage of infection and are major drivers of acute systemic diseases such as sepsis and peritonitis. In this context, conventional antibiotics are increasingly constrained by multidrug resistance, reduced permeability and energy-dependent efflux. An effective nanomaterial should ideally combine rapid bacterial contact, envelope disruption or energetic sensitization and improve local exposure to the partner antibiotic without substantially increasing the systemic burden [100]. Given this biological background, designs that adjust size and surface charge to promote rapid bacterial association and membrane perturbation, that use ion-releasing or redox-active cores to attenuate proton-coupled efflux and that protect particles with serum-stable, antifouling shells to preserve activity in inflammatory fluids are especially useful [176]. The combination with standard agents is not an afterthought but a core purpose, since permeability enhancement and energetic collapse allow dose-sparing regimens to regain bactericidal activity.

This logic is supported across representative platforms. Structurally engineered antimicrobial peptide polymers, which emulate host-defense peptides, disrupt bacterial membranes through multivalent contact and improve outcomes in murine infection models, including those of peritonitis caused by carbapenem-resistant Gram-negative pathogens [177]. Compared with antibiotics alone, mesoporous carriers that contain silver provide controlled ionic release and, when loaded with fluoroquinolones, accelerate bacterial clearance in mouse acute peritonitis models [100]. Zinc and copper oxide nanomaterials add catalytic oxidative antibacterial activity and have shown efficacy in selected in vivo infection models, although direct evidence in bloodstream infection settings remains limited [178]. Very small gold nanoclusters can add direct antibacterial activity against staphylococci and, in some studies, attenuate dysregulated inflammatory responses in infection-related models, suggesting that ultrasmall metal systems may combine bacterial killing with partial host-response modulation when exposure and clearance are appropriately controlled [179]. Across these examples, the common feature is not the material itself, but the way size, charge, surface stability and controlled oxidative or ionic stress are aligned with the pharmacology of the coadministered drug and with the exposure that can actually be achieved in an acute intraperitoneal or systemic infection setting. These examples address infection states in which bacteria remain relatively accessible to circulating or locally delivered therapeutics. However, once pathogens enter host cells or protected tissue compartments, antibacterial nanomaterials must overcome an additional set of barriers related to intracellular trafficking, endolysosomal sequestration, and compartment-specific drug exposure.

8.2. Intracellular infections

Although intracellular delivery addresses protected bacteria within host cells, many chronic and device-associated infections are dominated by extracellular communities embedded in biofilm matrices. These infections require nanomaterials that can penetrate, remodel, or locally activate structured extracellular polymeric substances. A substantial group of bacterial pathogens—including Mycobacterium tuberculosis, Salmonella enterica, and some S. aureus strains—survive or replicate inside macrophages and epithelial cells. Once internalized, they are partly protected from many antibiotics by compartmental sequestration, local pH changes, efflux activity, and stress-adapted slow-growing states [180]. In this context, a useful nanomaterial should first reach the infected phagocyte and then release its payload in response to endolysosomal conditions and, when needed, assist endosomal escape or provide an additional microbicidal stimulus within intracellular compartments [181]. Designs that combine receptor-guided uptake (for example, mannose or other macrophage-targeting ligands), acid- or enzyme-cleavable linkers that respond to phagolysosomal conditions, and serum-stable antifouling interfaces fit this biological problem well [182].

Examples from preclinical models are broadly consistent with this design logic. In cell-based models, solid-lipid nanoparticles loaded with fluoroquinolones markedly increase macrophage uptake and intracellular activity against Salmonella, whereas mannose-functionalized lipid nanoparticles improve alveolar macrophage targeting in pulmonary tuberculosis [183]. Mannose-decorated lipid or polymeric carriers exploit receptor-mediated endocytosis to concentrate payloads in M. tuberculosis-relevant macrophage targets and improve pulmonary targeting [182]. Gold nanoparticles functionalized with aptamers or antimicrobial peptides eliminate intracellular Salmonella in infected HeLa cells, indicating that targeting plus local delivery can overcome the need for an intracellular refuge [184]. Liposomal delivery systems extend this idea by improving the intracellular access of glycopeptides such as vancomycin in infected macrophages; biomimetic surface coatings may further support targeting in selected systems [185]. Platforms that add controlled intracellular ROS or other microbicidal stimuli can further reduce the intracellular bacterial burden while maintaining acceptable host cell viability in reported models [181]. These systems are connected not by a single material class but by the sequential alignment of targeting, triggered release, and intracellular exposure with the specific constraints of macrophage-resident or epithelium-resident infection.

8.3. Biofilm-associated infections

Biofilm formation is a major reason why chronic wounds, osteomyelitis, otitis media, and device-related infections respond poorly to conventional antibiotics [186]. Once bacteria are embedded in an extracellular polymeric substance (EPS), diffusion is hindered, the local pH and redox conditions change, and cells adopt a tolerant, low-metabolic state [187]. Host clearance is also reduced. In this setting, an antibacterial nanomaterial should address a different problem from acute planktonic disease: it should enter or remodel the matrix, concentrate antibacterial stress on site, and, ideally, resensitize embedded cells to clinically available drugs. Designs that use suitably small particles with tuned surface functionality that balance charge or display EPS-affinity motifs to improve intrabiofilm transport; that carry enzymatic shells to degrade polysaccharides or extracellular DNA; and that can be activated locally by light, acoustic energy, or magnetically actuated strategies in selected settings are therefore most relevant for identifying biofilm targets [188].

Preclinical studies illustrate how these principles work in practice. Silver- and zinc-based hydrogels applied to methicillin-resistant S. aureus skin infections can reduce the bacterial burden and accelerate wound closure, in part because the gel matrix maintains local contact and sustains metal-derived antibacterial stress at the colonized surface [189]. Near-infrared–activatable carbon-dot hydrogels used in infected bone or deep-tissue models combine photothermal or sonodynamic antibacterial effects with tissue-repair benefits [190]. In the oral cavity, iron oxide systems, which were originally developed for supplementation, have been repurposed to disrupt cariogenic biofilms and prevent lesion development in rodents [188]. With respect to indwelling devices, silver-coated urinary catheters have shown variable effects on early microbial colonization, whereas magnetically actuated iron oxide systems can mechanically disrupt established biofilms and facilitate subsequent clearance [191]. Across these examples, the decisive step is not simply “killing bacteria” but also creating matrix porosity, improving access, and applying antibacterial stress where systemic agents cannot accumulate. Platforms that integrate penetration, matrix remodeling and on-site activation can resensitize biofilm-resident cells to β-lactams, lipopeptides or glycopeptides and are therefore well aligned with current regimens for chronic and device-associated infections. However, many clinically refractory infections cannot be assigned to a single category. Biofilms frequently coexist with intracellular reservoirs, abscess-like niches, necrotic tissue, and poorly perfused compartments, which motivates a separate discussion of mixed and relapse-prone infections.

8.4. Mixed infections, tissue spread, and relapse-prone disease

Mixed and relapse-prone infections represent late-stage consequences of incomplete bacterial clearance, where tissue spread, residual bacterial reservoirs, and recurrent infection are often driven by multiple overlapping pathological niches. In these settings, extracellular biofilms, intracellular reservoirs, abscess-like niches, necrotic tissue, foreign-body surfaces, and poorly perfused tissue compartments may coexist. This spatial and physiological heterogeneity makes treatment failure difficult to attribute to a single mechanism and limits the predictive value of conventional planktonic susceptibility testing.

For nanomaterial design, the key requirements are not only stronger antibacterial activity but also spatially sustained and compartment-aware exposure. Local depots, injectable or in situ-forming hydrogels, mucoadhesive or tissue-adhesive carriers, magnetically guided systems, and ultrasound-, light-, or pH-responsive platforms may help maintain effective concentrations at poorly perfused infection interfaces. In relapse-prone models, efficacy should therefore be evaluated using bacterial burden reduction, tissue distribution, residual viable bacteria, recurrence after treatment withdrawal, histopathological repair, and host inflammatory injury rather than short-term killing alone.

Clinically relevant examples include chronic wound infection, osteomyelitis, implant-associated infection, catheter-associated infection, and pulmonary infection with mucus obstruction or biofilm-like aggregates. These conditions require models that reproduce tissue barriers, host proteins, polymicrobial communities, and incomplete source control. Nanomaterial strategies that combine local release, matrix remodeling, intracellular access, and host-directed immunomodulation are particularly relevant to this stage, but their translational value depends on whether they can reduce relapse without increasing local tissue toxicity or systemic accumulation.

8.5. Clinical translation and clinically evaluated antibacterial nanomaterial platforms

The final step of the cascade-oriented application framework is clinical translation, where antibacterial efficacy must be integrated with manufacturability, pharmacokinetics, safety, regulatory classification, and indication-specific endpoints. Compared with preclinical models, clinical translation places greater emphasis on reproducible critical quality attributes, batch comparability, sterilization, device compatibility, local and systemic exposure, and clinically meaningful outcomes. Material properties should be treated as pharmacokinetic variables rather than only formulation descriptors because size, surface chemistry, corona behavior, ligand density, and degradability jointly determine the biodistribution, immune clearance, tissue retention, target-site exposure, and feasibility of repeated dosing. Clinical experience with antibacterial nanomaterials has thus far concentrated on two relatively tractable areas: locally acting devices and dressings and inhaled or otherwise interface-focused drug products. Silver-containing or silver-coated dressings are now widely used in wound care; silver-alloy urinary catheters and silver-coated endotracheal tubes have been evaluated for the prevention of device-associated infection, and an inhaled liposomal formulation of amikacin has been approved for refractory Mycobacterium avium complex lung disease under limited-population indications [191,192]. These examples indicate that clinical translation is most plausible for locally acting or interface-focused products, particularly when infection-site exposure can be controlled, antimicrobial activity remains within a defined therapeutic window, and outcomes are assessed using prespecified microbiological and clinical endpoints. They also reported that clinical benefit requires close alignment among material function, exposure profile, target population, and endpoint selection.

Clinical experience has also revealed important limitations. Silver-alloy urinary catheters have produced heterogeneous results and do not support routine use across all patient groups, while dual-release liposomal ciprofloxacin has shown inconsistent efficacy in parallel phase III trials. These outcomes suggest that antimicrobial coatings or sustained-release nanocarriers are unlikely to succeed unless local exposure, patient selection, pathogen burden, dosing schedule, and clinical endpoints are defined for the intended indication. This variability highlights the need for more harmonized protocols—especially for externally triggered systems, where best-practice reporting should specify photosensitizer loading, actuator dose, and tissue exposure to allow comparison across centers [193].

For broader adoption, several nanospecific risks need to be managed: tight control of critical quality attributes across batches; quantitative control of ion and oxidative release within a defined window; characterization of protein-corona behavior in inflamed or infected matrices; and definition of pharmacokinetics in poorly perfused compartments such as chronic wounds or periprosthetic pockets. Equally important is the establishment of scalable, quality-by-design manufacturing routes that satisfy regulatory expectations for sterility, stability and reproducibility. Addressing these requirements will align preclinical signals with clinical decision-making and reduce the translational risk that has thus far limited the number of nanomaterial-based antibacterial products reaching routine practice. The selected clinically evaluated/approved platforms are summarized in Table 3.

Table 3.

Clinically evaluated/approved antibacterial nanomaterial platforms.

Nanomaterial System	Indication	Registry/primary source	Key Outcome	Status
Aquacel®Ag Hydrofiber dressing [194]	Surgical site infections	UMIN000043081	Superficial SSI reduced: 6.8% vs 11.4% (elective gastrointestinal surgery).	Randomized clinical trial
Aquacel®Ag Surgical dressing [195]	Knee arthroplasty	NCT02445300	Superficial SSI reduced: 0.8% vs 8.3% after MIS-TKA.	Randomized clinical trial
AQUACEL® Ag + Extra™	Venous leg ulcers	NCT05892341	12-week healing outcome under clinical evaluation.	Postmarket clinical study
Silver-alloy urinary catheters [191]	CAUTI prevention	NCT01803919	No significant reduction in symptomatic UTI; routine use not supported in SCI patients.	Randomized clinical trial
Silver-coated endotracheal tubes [192]	Ventilator-associated pneumonia	NCT00148642	Reduced VAP incidence and delayed time to VAP occurrence.	Randomized clinical trial
Arikayce®Liposomal amikacin [196]	Refractory MAC lung disease	NCT02344004	Improved culture conversion when added to guideline-based therapy.	Approved drug
Ciprofloxacin liposome [197]	Non-CF bronchiectasis with chronic P. aeruginosa infection.	NCT02104245	One phase III trial met the primary endpoint, one did not; pooled analysis was not statistically significant.	Phase III
AgTive® CVC [198]	Prevention of catheter-related bloodstream infection	NCT00337714	No significant reduction in colonization, CRBSI incidence, or ICU mortality; routine adjunctive use not recommended.	Randomized clinical trial

Note: This table summarizes nanomaterial platforms that have entered clinical trials or obtained regulatory approval. Clinical trial identifiers correspond to official registries, including UMIN, ClinicalTrials.gov, FDA databases and PubMed records. The listed examples illustrate translational progress across a spectrum of applications, ranging from wound management and device-associated infections to inhalable formulations for mycobacterial disease. Status: Approved/Cleared/Marked product/Randomized clinical trial/postmarket clinical study/phase III inhaled drug trial.

9. Translational challenges and next-generation directions

Despite rapid progress, antibacterial nanomaterials still face three major translational gaps: limited predictability of simplified in vitro assays for human infection sites, insufficient control over biodistribution and long-term safety, and inadequate standardization of biofilm and relapse models. Future development should move beyond material novelty toward indication specific, quantitatively benchmarked, and exposure-controlled design. The most transformative advances are likely to come from data-driven material optimization, living or biomimetic hybrid systems, and cascade-responsive platforms that integrate infection-derived cues with external activation and microenvironment remodeling.

9.1. Data-driven design and quantitative benchmarking

A first priority is to shift from descriptive material screening to data-driven and quantitatively benchmarked design. At present, cross-study comparisons are limited by differences in strains, culture media, biofilm maturity, exposure time, dose metrics, and endpoints. Future studies should report a minimal quantitative dataset, including MIC or MBC shifts, time-kill kinetics, MBIC or MBEC values, biofilm biomass and viable-bacteria reduction, intracellular bacterial clearance, local pharmacokinetics, cytotoxicity, hemocompatibility, and relapse after treatment withdrawal. When these metrics are standardized, machine learning and structure–activity modeling can be used to connect particle size, shape, surface charge, ligand density, degradation behavior, and release kinetics with antibacterial efficacy and host safety. Such data-driven frameworks would help define design windows before expensive animal studies, but their value depends on standardized descriptors, comparable assays, and transparent reporting of both positive and negative results.

Biofilm models require particular standardization because they strongly determine translational predictability. Static, short-term, single-species biofilms grown on plastic surfaces often fail to reproduce the architecture, host–protein conditioning, oxygen and nutrient gradients, immune pressure, mechanical forces, vascular limitation, tissue damage, and polymicrobial ecology of chronic human infections. This mismatch partly explains why strong antibiofilm activity in vitro or in small-animal models may not translate into durable efficacy in human wounds, implants, lungs, oral biofilms, or catheter-associated infections. Future studies should incorporate clinical isolates, mature and chronic biofilms, multispecies communities when clinically relevant, flow or shear conditions, tissue-like or implant-relevant substrates, and host-derived matrices such as serum, wound fluid, sputum, fibrin, collagen, or extracellular DNA. This need for standardization is also evident in oral device-associated settings, where antibacterial nanoparticles in clear overlay orthodontic appliances show promising antibiofilm effects but vary substantially in application protocols, retention, and coating stability [199]. Endpoints should extend beyond biomass staining to include viable CFU, MBEC, spatial penetration, matrix composition, local pharmacokinetics, residual bacteria after treatment, relapse after treatment withdrawal, inflammatory injury, tissue repair, and compatibility with standard antibiotics.

9.2. Living, biomimetic, and hybrid antibacterial materials

Living and hybrid antibacterial materials represent a second transformative direction. Engineered probiotics, bacteria-derived vesicles, immune-cell-mimetic carriers, enzyme-functionalized matrices, and biomaterial-cell hybrids may provide adaptive sensing, local persistence, and microenvironment-responsive activity that inert carriers cannot easily achieve. These systems could be particularly useful for chronic wounds, mucosal infections, and recurrent biofilm-associated disease, where infection is shaped by local immunity, tissue repair, nutrient gradients, and microbial community structure. Their translation, however, will require stringent control of viability, genetic stability, immunogenicity, containment, batch consistency, and reversibility of activity.

9.3. Cascade-responsive systems and infection-microenvironment remodeling

A third direction is the design of cascade-responsive platforms that combine endogenous infection cues with externally controlled activation. Infected tissues often contain acidic pH, bacterial or host proteases, oxidative stress, hypoxia, high ionic strength, and dense extracellular matrices. Materials that respond sequentially to these cues and then amplify antibacterial activity through light, ultrasound, magnetic fields, or localized catalytic reactions may improve spatial precision and reduce off-target injury. Equally important is the ability to reshape the infection microenvironment, for example, by loosening extracellular polymeric substances, improving antibiotic penetration, modulating excessive inflammation, or promoting tissue repair. This microenvironment-oriented strategy should also include immune recalibration because persistent inflammation and impaired repair often contribute to relapse in chronic wounds and biofilm-associated infections. The key challenge is to demonstrate, in disease-relevant and relapse-sensitive models, that cascade responsiveness improves target-site exposure, biofilm penetration, immune balance, tissue repair, and therapeutic index rather than merely increasing functional complexity.

10. Conclusions

Antibacterial nanomaterials provide an interface-centered strategy for antibiotic-resistant infections by targeting bacterial envelopes, biofilm matrices, intracellular reservoirs, infected tissues, and host immune microenvironments. This Review organizes these strategies through an infection-cascade framework that links biological barriers to material design modules, quantitative readouts and translational checkpoints. The field should now prioritize mechanism-guided design, disease-relevant biofilm and infection models, standardized efficacy and safety metrics, lesion-level pharmacokinetics, and reproducible quality attributes for manufacturing and regulatory translation. Progress in these areas will determine whether antibacterial nanomaterials can move from promising experimental platforms to clinically useful interventions for resistant, biofilm-associated, intracellular, and recurrent infections. In the near term, locally accessible infections, including wound, dental, orthopedic, and device-associated infections, may provide the most realistic translational entry points because nanomaterial exposure, activation, retrieval, and safety monitoring can be more tightly controlled than broad systemic indications

Ethics statement

Not applicable.

Use of AI statements

None.

Funding

This manuscript has not received any funding or financial support.

CRediT authorship contribution statement

Luanbiao Sun: Data curation, Writing – original draft, Writing – review & editing. Yicheng Zhao: Writing – original draft, Writing – review & editing. Yang Gao: Data curation. Shuohui Gao: Data curation, Writing – original draft, Writing – review & editing. Li Wang: Formal analysis, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the Supplementary data to this article.

Data availability

Data will be made available on request.