From constitutive killing to microenvironment-activated antimicrobial activity: a critical narrative review of antimicrobial dental materials for caries prevention

Introduction

Dental caries is a multifactorial, diet-modulated, biofilm-mediated disease driven by a persistent imbalance between demineralization and remineralization. Frequent sugar exposure can disrupt biofilm homeostasis and favor a cariogenic community, supporting biofilm management and dietary control as central preventive strategies (Huang and Zandoná, 2025). Dental caries remains the most prevalent condition evaluated by the Global Burden of Disease Study (Centers for Disease Control and Prevention, 2024; GBD 2021 Oral Disorders Collaborators, 2025).

Restorative treatment repairs cavitated tooth structure but does not eliminate the underlying biofilm-mediated disease process. Secondary caries at restoration margins is a major cause of restoration failure, accounting for more than 40% of failures overall and up to 73.9% of composite replacements in long-term studies (Kopperud et al., 2012; Featherstone, 2022). Biofilm-retentive prosthetic and orthodontic appliances create additional caries-prone sites (Preshaw et al., 2011). In orthodontic patients, a meta-analysis of 57 studies involving 9,101 individuals reported white spot lesions in 55% of treated versus 29% of untreated patients, with bonded appliances associated with approximately sevenfold higher odds (Hussain et al., 2025). These settings provide a clinical rationale for materials that actively interfere with cariogenic biofilms rather than functioning only as inert restorative or appliance components.

Accordingly, restorative-material design has progressed from largely inert formulations to antimicrobial and multifunctional bioactive systems that may combine microbial control with remineralization (Melo et al., 2023). Remineralizing agents such as nanohydroxyapatite have shown efficacy in early-lesion models and controlled clinical studies (Amaechi et al., 2019a; Amaechi et al., 2025), but bioactive material design must balance biological activity against esthetic and physicomechanical requirements (Melo et al., 2023).

This narrative review examines seven classes of caries-relevant antimicrobial or antifouling strategies. Six are material-intrinsic: quaternary ammonium compounds (QACs)/quaternary ammonium polyethyleneimine (QPEI) nanoparticles, metallic nanoparticles, photocatalytic titanium-based materials, graphene-based materials, zwitterionic polymers, and biomimetic nanozymes. They are compared by mode of activity (diffusible, contact-dependent, or antifouling) and activation trigger (constitutive, light-activated, or biofilm-microenvironment-responsive).

Antimicrobial peptides constitute the seventh class considered in this review. Unlike the six material-intrinsic classes, their activity is encoded by peptide sequence and molecular design rather than arising from an intrinsic physicochemical property of a dental material. C16G2, a specifically targeted antimicrobial peptide (STAMP) directed against Streptococcus mutans, is emphasized because it has progressed further clinically than other caries-relevant antimicrobial peptides. Bioactive glass, smart pH-responsive polymeric delivery systems, organoselenium-based materials, and emerging CRISPR-based targeted antimicrobial platforms are discussed briefly outside the seven-class framework because they either do not represent distinct material-intrinsic antimicrobial chemistries or have a more limited caries-focused evidence base.

The review focuses primarily on S. mutans, Candida albicans, cariogenic lactobacilli, and caries-relevant multispecies biofilms. C. albicans is included because its interaction with S. mutans can enhance biofilm cariogenicity and enamel demineralization (Falsetta et al., 2014). Microbiological outcomes—including organism counts, biofilm biomass, metabolic activity, and plaque accumulation—are treated as surrogate evidence unless accompanied by a tooth- or disease-level anticaries endpoint.

This is a narrative, mechanism-driven review rather than a PRISMA-guided systematic review; no protocol was registered and no formal quality-appraisal instrument was applied. Articles were selected for mechanistic relevance and translational value, so statements about evidence gaps refer to the literature included in this synthesis. For cross-class comparison, Figure 1 maps the six material-intrinsic classes by mode of activity (Ramburrun et al., 2021) and activation trigger (Montoya et al., 2023). The framework is a comparative heuristic, not a mutually exclusive taxonomy: metallic nanoparticles, graphene-based systems, and TiO₂-containing materials can exhibit overlapping or formulation-dependent mechanisms. Placement therefore reflects the predominant mechanism and activation condition emphasized in the studies reviewed.

The categories are not mutually exclusive; placement reflects the predominant mechanism and activation condition emphasized in the cited studies, and individual formulations may span more than one category.

Figure 1 highlights that most material classes are constitutively active, whereas photocatalytic titanium-based materials and biomimetic nanozymes depend on external or microenvironmental activation. It also shows that the literature has emphasized microbial killing more than antifouling, with zwitterionic polymers representing the principal non-killing approach.

Figure 2 distills three recurring interfacial mechanisms: contact-mediated membrane disruption, reactive oxygen species (ROS) generation, and an antifouling hydration barrier. QAC/QPEI systems primarily illustrate contact-mediated killing; photocatalytic titanium-based materials and nanozymes illustrate catalytic ROS generation; and zwitterionic polymers resist initial attachment through surface hydration. Metallic nanoparticles and graphene-based materials can combine more than one of these mechanisms. This mechanistic distinction also informs the antimicrobial-resistance and stewardship considerations discussed later.

The following sections examine each material class using an integrated mechanism-and-evidence format, with detailed concentrations and quantitative outcomes consolidated in the corresponding tables. Class-specific critical evaluations are incorporated into the Evidence Summary or concluding portion of each material section to interpret evidence quality, safety, translational status, and remaining limitations. Throughout, microbiological surrogate outcomes are distinguished from direct anticaries endpoints such as enamel demineralization, lesion progression, caries arrest, or caries incidence.

QACs and QPEI nanoparticles

QACs are among the oldest antibacterial chemistries studied in dentistry. They share a permanently cationic nitrogen center that disrupts the bacterial cell envelope through electrostatic interactions rather than through a specific molecular target (Imazato et al., 1994). In caries preventive dental materials, QACs have been incorporated in three main forms: small, diffusible surfactants with limited oral substantivity; polymerizable QAC methacrylate monomers, ranging from methacryloyloxydodecylpyridinium bromide (MDPB) to dimethylaminoalkyl (DMA) methacrylates with varying alkyl chain lengths, that become covalently incorporated into the resin network; and QPEI, in which multiple QAC groups are attached to a cross-linked nanoparticle carrier (Beyth et al., 2006).

The two immobilized subclasses—polymerizable QAC monomers and QPEI nanoparticles—were developed through distinct research lineages (Drejka et al., 2024). Despite their different origins, both rely on the same underlying electrostatic mechanism and are therefore considered together in this review.

Mechanism and caries-relevant antimicrobial evidence

All QAC subclasses share the same basic mechanism of action: the permanently cationic quaternary nitrogen groups bind to negatively charged phospholipids and teichoic acids in the bacterial envelope, disrupting membrane integrity, promoting cytoplasmic leakage, and ultimately causing cell death (Beyth et al., 2006; Zhang et al., 2016). In the immobilized subclasses, this activity occurs at the material surface without release of the antimicrobial compound. For example, MDPB-containing resin released no detectable MDPB after curing yet retained contact-dependent activity against S. mutans (Imazato et al., 1994; Imazato, 2003).

Across polymerizable QAC homologues, antibacterial activity generally increased with alkyl-chain length up to CL16 and declined at CL18, a pattern attributed to greater membrane interaction followed by partial shielding of cationic groups in the longest chains (Tiller et al., 2001; Li et al., 2013; Zhang et al., 2016). DMAHDM (CL16) was therefore the most active homologue tested. QPEI achieves high cationic charge density through multiple quaternary ammonium groups on a cross-linked nanoparticle, with efficacy influenced by particle distribution and surface accessibility; controlled neutralization and surface treatment can reduce the loading required for activity (Beyth et al., 2006; Shvero et al., 2015; Zaltsman et al., 2016).

Despite these differences in molecular architecture, both subclasses share the same fundamental design constraint: antimicrobial activity depends on presenting enough accessible, unshielded cationic groups at the material surface.

Monomeric quaternary ammonium methacrylates

Imazato’s foundational studies established that MDPB exhibits strong contact-dependent activity against S. mutans, with no detectable leaching and no adverse effect on bond strength (Imazato et al., 1994; Imazato, 2003). Longer-chain QAC monomers generally showed greater antibacterial activity, and DMAHDM-containing remineralizing composites produced substantial reductions in viable bacteria and metabolic activity without compromising the measured mechanical properties (Zhang et al., 2016). Concentrations and quantitative outcomes are summarized in Table 1. These findings demonstrate antibacterial activity, but microbiological reductions should not by themselves be interpreted as evidence that the formulation prevents enamel demineralization or clinical caries.

Table 1. Antibacterial, antifungal, and cytotoxicity evidence for monomeric quaternary ammonium compounds in caries-relevant applications.

Outcomes summarized as antibacterial/antifungal effects are microbiological surrogates unless a caries-specific endpoint is explicitly reported.

In a serial-passage study, repeated exposure to a DMAHDM-containing composite did not produce a detectable increase in antimicrobial resistance in S. mutans under the conditions tested, whereas chlorhexidine selected for reduced susceptibility in multiple oral bacterial species (Wang S. et al., 2018). Comparable resistance-selection data were not identified for QPEI. Evidence regarding species selectivity also remains limited: DMAHDM altered the relative abundance of S. mutans within a biofilm community, but it remains unclear whether this reflected differential susceptibility or changes in interspecies competition after overall biomass reduction (Wang et al., 2019). The corresponding formulation and quantitative findings are provided in Table 1.

QPEI nanoparticles

Beyth and colleagues demonstrated that QPEI-containing resin composites exert strong antibacterial activity against S. mutans without compromising the measured flexural properties (Beyth et al., 2006). Subsequent studies reported favorable surface properties and biocompatibility (Yudovin-Farber et al., 2008), lower-loading synthetic variants (Zaltsman et al., 2016), sustained activity over time (Yudovin-Farber et al., 2010; Shvero et al., 2015), and reproducibility across composite systems (Pietrokovski et al., 2016; Chladek et al., 2023). A human in situ study also demonstrated reduced biofilm vitality (Beyth et al., 2010). Detailed concentrations and quantitative outcomes are summarized in Table 2. However, because QPEI has not been evaluated in randomized controlled trials assessing caries incidence or restoration survival, its clinical evidence remains limited. The in situ biofilm response is a surrogate microbiological endpoint and does not establish anticaries efficacy in the absence of a demineralization or caries outcome.

Table 2. Antibacterial and antifungal evidence for QPEI nanoparticles and structurally related quaternary ammonium systems in caries-relevant applications.

The two C. albicans rows (quaternized PEI, non-dental chemistry; C12BDMA-Cl, a structurally related but distinct compound) are indirect, hypothesis-supporting evidence rather than direct data for the dental QPEI nanoparticle platform itself, which has no C. albicans data of its own; see text. These antimicrobial outcomes should not be interpreted as direct evidence of anticaries efficacy. MIC, minimum inhibitory concentration.

QPEI performance is formulation-dependent: higher loading can increase solubility and compromise mechanical properties (Pietrokovski et al., 2016; Barszczewska-Rybarek et al., 2021). Applications include glass ionomer cements, temporary restoratives, endodontic sealers, and orthodontic models (Beyth et al., 2012; Abramovitz et al., 2013; Kesler Shvero et al., 2013; Barros et al., 2014b; Barros et al., 2014a; Sharon et al., 2018). Because C. albicans can interact synergistically with S. mutans, antifungal findings from related quaternary ammonium chemistries are also relevant (Gao et al., 2007; Falsetta et al., 2014; Chen H. et al., 2017; Chen et al., 2020b; Aldulaijan et al., 2024). Formulation-specific concentrations and outcomes are summarized in Tables 1 and 2.

Evidence summary

The antibacterial, antifungal, and cytotoxicity evidence for monomeric quaternary ammonium methacrylates is summarized in Table 1, while Table 2 presents the corresponding evidence for QPEI nanoparticles and closely related quaternary ammonium chemistries.

The absence of bacterial resistance development with DMAHDM, in contrast to chlorhexidine, represents a separate safety-relevant consideration (Wang S. et al., 2018). Thus, the two immobilized subclasses should not be regarded as interchangeable. Their distinct toxicity profiles and evidence bases warrant separate evaluation. Antifungal findings from structurally related quaternized PEI systems should not be interpreted as direct evidence for the dental QPEI nanoparticle platform.

Overall, QAC/QPEI systems have a comparatively mature restorative-incorporation literature, including human in situ evidence for QPEI, but most outcomes remain microbiological rather than caries-specific (Beyth et al., 2010). Their main translational constraints are formulation-dependent efficacy, mechanical trade-offs at higher loading, and an incompletely defined therapeutic window; toxicity data from CTAB or DODAB should not be generalized to polymerizable DMAHDM/DMADDM or dental QPEI formulations (Yudovin-Farber et al., 2008; Yudovin-Farber et al., 2010; Pietrokovski et al., 2016; Zhang et al., 2016; Chen H. et al., 2017; Wang S. et al., 2018; Chen et al., 2020b; Chladek et al., 2023; Szymczak-Pajor et al., 2025). Contact-dependent activity may also be influenced by salivary pellicle, although QPEI retained substantial antibiofilm activity during whole-saliva exposure (Beyth et al., 2010; Li et al., 2014).

Metallic nanoparticles

Metallic and metal oxide nanoparticles are among the most extensively studied antimicrobial additives for controlling cariogenic biofilms. Their high surface-area-to-volume ratio, surface reactivity, and, for some formulations, ion-release properties contribute to antimicrobial activity in dental adhesives, composites, and cements (Chen et al., 2020a). This section focuses primarily on elemental silver nanoparticles (AgNPs) and metal oxide nanoparticles such as zinc oxide (ZnO), magnesium oxide (MgO), and copper oxide (CuO), whose reported antimicrobial activity is constitutive and does not require deliberate light activation. Titanium-based systems whose primary antimicrobial mechanism depends on photocatalytic activation are considered separately in the following section. A non-photocatalytic TiO₂ formulation is included here only because the cited study evaluated antibacterial activity without attributing the observed effect to light-induced photocatalysis.

Mechanisms and caries-relevant antimicrobial evidence

Silver nanoparticles act through at least two mechanisms though these have not always been experimentally distinguished. Direct interaction with the bacterial surface increases membrane permeability and can lead to cell death, whereas Ag⁺ ions released from the particles can independently interfere with metabolic and enzymatic processes (Corrêa et al., 2015). Zinc oxide nanoparticles add oxidative stress to a similar contact-mediated mechanism. In S. mutans biofilms, ZnO nanoparticles increase intracellular ROS while disrupting membrane potential, energy metabolism, and extracellular polysaccharide synthesis, indicating activity against multiple cellular processes rather than a single molecular target (Emram et al., 2025).

TiO₂ nanoparticles, discussed separately below as a photocatalytic material class, also exhibit baseline antibacterial activity through surface-associated oxidative stress, even in the absence of strong light activation (Sodagar et al., 2017). Magnesium oxide and copper oxide nanoparticles appear to act through a combination of alkalinity modulation, ion release, and oxidative stress, although much of the available mechanistic evidence is derived from narrative reviews rather than dedicated mechanistic studies (Ma et al., 2022; Sharifian et al., 2023). Nanoparticles containing zinc or magnesium have also been proposed to modify the local pH and thereby reduce demineralization. This represents an indirect anticaries effect that is distinct from direct bacterial killing (Chen et al., 2020a).

When incorporated into adhesives, composites, cements, sealants, and topical formulations, metallic and metal oxide nanoparticles have reduced bacterial adhesion or biofilm formation relative to unmodified controls in multiple in vitro studies (Bolenwar et al., 2023). Silver and zinc oxide nanoparticles account for much of the restorative-incorporation evidence, including flowable composites, self-etch adhesives, and glass ionomer cements (Kasraei et al., 2014; Porter et al., 2020; Wang et al., 2022; Wassel and Allam, 2022). TiO₂ nanoparticles have also been evaluated in an orthodontic composite without specified photoactivation and are included here because the reported antibacterial effect was not attributed to photocatalysis (Sodagar et al., 2017). Formulation-specific concentrations and quantitative outcomes are summarized in Table 3, allowing the text to focus on the overall evidence pattern and its translational interpretation.

Table 3. Antibacterial evidence for metallic nanoparticles in caries-relevant applications.

Antibacterial endpoints are distinguished from direct anticaries outcomes such as caries arrest or enamel demineralization.

Topical applications have substantially more mature clinical evidence than nanoparticle-containing restorative materials. Nano silver fluoride (NSF), which combines silver nanoparticles with fluoride, was more effective than control in arresting pediatric caries at both 5- and 12-month follow-up in randomized trials (Nagireddy et al., 2019). NSF also showed caries-arrest efficacy comparable to silver diamine fluoride (SDF), with less tooth discoloration (Quritum et al., 2024). In contrast, metallic nanoparticles incorporated into restorative materials have not reached a comparable level of clinical validation. A systematic review of antimicrobial restorative materials found consistent evidence of laboratory antimicrobial activity but limited evidence that these effects translate into reduced caries clinically (do Amaral et al., 2016). Thus, within the evidence considered here, randomized clinical trials evaluating a direct caries-arrest endpoint were available for nano silver fluoride (Nagireddy et al., 2019; Quritum et al., 2024). However, these findings apply to a topical formulation and should not be extrapolated to metallic nanoparticles incorporated into restorative materials. This distinction is important: the restorative-material studies summarized above primarily demonstrate antimicrobial activity, whereas the NSF trials measured caries arrest and therefore provide direct anticaries evidence (Nagireddy et al., 2019; Quritum et al., 2024).

The antimicrobial activity of metallic nanoparticles also extends to C. albicans. Silver- and zinc oxide-based dental formulations have shown substantial inhibition or disruption of fungal biofilms, and combined silver-zinc oxide-chitosan systems have demonstrated activity against both bacterial and fungal components (Mousavi et al., 2020; Apip et al., 2021; Subramaniam et al., 2024). The quantitative effects are summarized in Table 3. These findings indicate that antibacterial and antifungal effects do not necessarily parallel one another within the same formulation. However, these studies did not evaluate caries-specific clinical outcomes; reductions in fungal or bacterial biofilm therefore remain microbiological outcomes and should not be interpreted as evidence of caries prevention without a tooth-level demineralization or caries endpoint.

Evidence summary

The caries-relevant antibacterial evidence for metallic nanoparticles discussed above is summarized in Table 3.

Metallic nanoparticles combine broad antimicrobial activity with extensive formulation flexibility, but clinical maturity is uneven. Topical nano silver fluoride has reached randomized trials with direct caries-arrest endpoints (Nagireddy et al., 2019; Quritum et al., 2024), whereas restorative-incorporated AgNP and ZnO systems remain largely preclinical. Biocompatibility is strongly dependent on particle size, concentration, surface chemistry, ion release, and matrix composition, and current efficacy and toxicity datasets are generally not concentration-matched; therefore, a formulation-specific therapeutic window cannot yet be defined reliably (Corrêa et al., 2015; Tabari et al., 2017; Emram et al., 2025).

Photocatalytic titanium-based materials

This section addresses titanium-based materials designed or evaluated for light-induced photocatalytic antimicrobial activity, distinguishing them from TiO₂ formulations tested without specified photoactivation (Sodagar et al., 2017). With appropriate irradiation, photocatalysts generate ROS catalytically rather than by releasing a finite antimicrobial payload (Mohammadi et al., 2025; Qi et al., 2025).

Photocatalytic mechanism and caries-relevant antimicrobial evidence

Photoexcited TiO₂ generates electron-hole pairs that produce hydroxyl radicals, superoxide, and related ROS, causing oxidative damage to bacterial membranes, proteins, and nucleic acids. Because this is a multi-target oxidative mechanism rather than a single molecular interaction, conventional target-specific resistance may be less readily selected.

Unmodified TiO₂ is limited by ultraviolet-dependent activation and rapid electron-hole recombination. Nitrogen doping can extend absorption into the visible range, whereas metal dopants such as silver, copper, bismuth, strontium, or gold can improve charge separation; some metal-containing systems may also add ion-mediated antimicrobial effects (Asahi et al., 2001).

Doped TiO₂ has shown visible-light antimicrobial activity, and a systematic review of TiO₂-coated orthodontic brackets found pooled effects against S. mutans, L. acidophilus, and C. albicans despite substantial heterogeneity (Gupta et al., 2013; Solanki et al., 2023). Antifungal activity against C. albicans has also been reported in denture-related and 3D-printed platforms (Abdulrazzaq Naji et al., 2018; Moradpoor et al., 2021; Ahmed et al., 2023; Altarazi et al., 2024).

The effectiveness of ROS-generating materials may be limited by the extracellular polymeric substance (EPS) matrix of mature biofilms. EPS components can react with short-lived hydroxyl radicals and singlet oxygen, potentially quenching these species before they reach bacterial cells (da Cruz Nizer et al., 2024). Accordingly, activity measured against planktonic bacteria or relatively thin biofilms may overestimate the activity achievable against mature cariogenic biofilms.

Doped TiO₂ dental resins and adhesives have shown activity against S. mutans under irradiated and, in some formulations, non-irradiated conditions; dark activity was attributed primarily to inherent nanoparticle toxicity rather than photocatalysis (Poosti et al., 2013; Zane et al., 2016; Esteban Florez et al., 2018; Zhao et al., 2023). Functionalization can also support durable filler-matrix interfaces without compromising the measured sorption, solubility, or mechanical properties (Esteban Florez et al., 2020b; Esteban Florez et al., 2020a; Hiers et al., 2022). Quantitative outcomes are summarized in Table 4.

Table 4. Antibacterial evidence for titanium-based photocatalytic materials in caries-relevant applications, including antifungal evidence against C. albicans.

*RCT, randomized controlled trial.

The principal unresolved issues are translational: durability of dopants or metal loading, formulation-specific biocompatibility, and whether clinically relevant sites receive sufficient activating light.

Gold- or platinum-loaded monosodium titanates have also suppressed bacterial growth, with nanoscale formulations outperforming micron-scale counterparts and evidence of species-dependent susceptibility (Chung et al., 2011; Eiampongpaiboon et al., 2015; Theda et al., 2018). Tested adhesive formulations did not significantly impair bond strength or microleakage (Deng et al., 2016); formulation details are provided in Table 4.

Orthodontic appliances: clinical-trial evidence

Photocatalytic TiO₂ has progressed furthest clinically in orthodontics. A split-mouth trial of nitrogen-doped TiO₂-coated brackets reduced plaque-associated S. mutans at 30 and 60 days, although the effect declined thereafter; a 90-day in vitro study reported more sustained activity (Salehi et al., 2018; Monica and Padmanabhan, 2022). Importantly, the clinical outcome was microbiological and did not establish prevention of white spot lesions, demineralization, or caries (Monica and Padmanabhan, 2022).

Silver-co-doped TiO₂ coatings also reduced S. mutans and Porphyromonas gingivalis adhesion and biofilm formation in vitro (Fatani et al., 2017). TiO₂-coated nickel–titanium archwires showed significantly less S. mutans adhesion than uncoated wires after one month of intraoral exposure; however, substantial delamination of the coating occurred during the same period (Venkatesan et al., 2020).

Intraoral light access

Light availability is a central translational constraint. Exposure is relatively favorable on accessible buccal, labial, and occlusal surfaces and around buccally bonded orthodontic appliances, which are also the sites represented in the available clinical evidence (Fatani et al., 2017; Salehi et al., 2018; Venkatesan et al., 2020; Monica and Padmanabhan, 2022).

Removable prostheses can be irradiated extraorally under controlled conditions, consistent with the concentration of antifungal evidence in denture substrates (Abdulrazzaq Naji et al., 2018; Moradpoor et al., 2021; Ahmed et al., 2023; Altarazi et al., 2024). By contrast, proximal, subgingival, deep fissure, cervical, and subsurface restorative sites may receive little light, creating a mismatch between photocatalytic activation and several caries-prone locations.

Intraoral irradiance at these candidate sites has not been directly quantified in the studies reviewed. Interpretation is further complicated because violet-blue light itself can suppress S. mutans biofilms and reduce enamel or dentin demineralization without a photocatalyst (Felix Gomez et al., 2018; Felix Gomez et al., 2019). Thus, light-only controls are essential when attributing antibacterial or anticaries effects to photocatalysis.

Visible-light sensitization through nitrogen doping can broaden activation conditions on exposed surfaces but cannot overcome absent illumination at inaccessible sites (Asahi et al., 2001).

Near-infrared upconversion offers a more experimental solution: NaYF₄:Yb,Tm/TiO₂ core-shell particles can convert 980-nm irradiation into shorter-wavelength emission that activates TiO₂ (Mančić et al., 2023). This concept remains outside dentistry and has not established whether proposed selective effects persist under NIR excitation.

A pragmatic alternative is to restrict photocatalytic indications to readily illuminated sites, such as orthodontic appliances, sealants, removable prostheses, and anterior facial restorations. Patient-worn LED devices could extend exposure, but introduce compliance and have not been specifically evaluated for photocatalytic restorative materials.

Combining photocatalysis with constitutive activity may reduce dependence on illumination: silver- or copper-containing systems can add ion-mediated effects, and nitrogen-doped TiO₂ has shown residual dark activity (Esteban Florez et al., 2018). Until irradiance is measured at clinically relevant sites, however, ‘light-activated’ should be regarded primarily as an experimental condition rather than an assured in vivo exposure state.

Light activation, oral biofilm ecology, and selective inhibition

A 2022 AADOCR/CADR conference abstract proposed selective, light-induced inhibition of S. mutans by gold-titanate rather than nonspecific killing; because this evidence remains an abstract, it should be interpreted cautiously (Huang et al., 2022).

The reported system generated more hydrogen peroxide under dental LED activation and inhibited S. mutans while preserving tested commensal streptococci, conceptually mimicking peroxide-mediated ecological antagonism in oral biofilms (Huang et al., 2022).

This apparent selectivity remains preliminary because it was demonstrated in monoculture/co-culture experiments rather than intact multispecies biofilms and has not yet been independently replicated in a peer-reviewed full-length study.

Evidence summary

Table 4 groups the caries-relevant antibacterial evidence discussed above according to application—adhesive resins, orthodontic coatings, and titanate-based materials—and also summarizes the available antifungal evidence against C. albicans.

Photocatalytic titanium-based materials provide externally triggered ROS generation, but efficacy depends on light access and durable surface activity. Human evidence is limited to an orthodontic bacterial endpoint rather than caries prevention (Monica and Padmanabhan, 2022), and matched efficacy-toxicity data remain insufficient to define a robust therapeutic window (Chen et al., 2015; Zane et al., 2016; Esteban Florez et al., 2020a).

Graphene-based materials

Graphene oxide (GO) and its derivatives, including formulations incorporating metal nanoparticles or nucleic acids, represent another class of antimicrobial materials with potential applications in caries prevention. Unlike the photocatalytic titanium-based materials discussed elsewhere in this review, which rely primarily on light-induced ROS, GO has an intrinsic physical antibacterial mechanism: its two-dimensional nanosheets have sharp edges that can disrupt bacterial membranes upon direct contact. The extent to which this activity has progressed toward clinical translation remains uncertain, as discussed in a recent review of graphene-based materials in caries and periodontal disease (Nizami et al., 2022).

Mechanisms and caries-relevant antimicrobial evidence

GO’s antibacterial activity is generally attributed to two mechanisms that may operate concurrently: physical membrane disruption and oxidative stress. Sharp-edged GO nanosheets can damage the S. mutans envelope and cause cytoplasmic leakage (He et al., 2015), whereas ROS-mediated damage may affect bacterial DNA and proteins without requiring external light activation. Their relative contributions vary with synthesis and surface functionalization; for example, zinc oxide nanorods on graphene nanoplatelets acted predominantly through mechanical damage (Zanni et al., 2016), and oxidative activity has not consistently tracked with antibacterial potency in non-dental models (Liu et al., 2011). GO may also interfere with quorum sensing and adhesion and bind calcium at the enamel surface (Nizami et al., 2022). Quantitative antimicrobial concentrations and outcomes are summarized in Table 5.

Table 5. Antimicrobial evidence for graphene oxide and its derivatives in caries-relevant applications.

MIC, minimum inhibitory concentration.

Much of the quantitative evidence against cariogenic organisms involves GO combined with a second antimicrobial component rather than unmodified GO. GO-ZnO, GO-Ag, and GO-Cu systems have reduced S. mutans metabolic activity, biofilm formation, EPS production, or viable counts, while some formulations have also shown preservation of material properties or reduced enamel mineral loss (Kulshrestha et al., 2014; Wu et al., 2018; Chen J. et al., 2020; Mao et al., 2021). Because these studies used different substrates and formulations, their concentrations and quantitative outcomes are summarized in Table 5 rather than repeated in the text. Notably, the reduced-GO/Ag enamel model included a caries-relevant mineral endpoint, whereas several other studies relied primarily on microbiological surrogates (Kulshrestha et al., 2014; Wu et al., 2018; Chen J. et al., 2020; Mao et al., 2021).

A structurally distinct strategy uses GO as a delivery vehicle for genetic material rather than as the primary antimicrobial agent. GO complexed with polyethylenimine and an antisense vicR-expressing plasmid downregulated virulence-associated genes in S. mutans, reduced EPS synthesis, and impaired biofilm aggregation, with cytotoxicity evaluated in parallel (Wu et al., 2020). The tested concentrations are provided in Table 5.

GO studies remain dominated by S. mutans despite the polymicrobial nature of caries. Limited C. albicans evidence includes inhibition by graphene-coated titanium and additive activity of a GO-fluconazole formulation; a 2025 scoping review likewise noted broad antimicrobial signals but insufficient definitive toxicity and biocompatibility data (Asadi Shahi et al., 2019; Agarwalla et al., 2021; Martuci et al., 2025).

Evidence summary

The caries-relevant antimicrobial evidence for GO and its derivatives discussed above is summarized in Table 5.

Surface roughness and the antibacterial activity of GO

Because GO activity can depend on nanosheet edges, surface roughness is a relevant dental concern. Available studies do not show a simple trade-off: functionalized GO incorporated into denture acrylic up to tested levels did not significantly increase roughness, and other GO-containing dental materials retained acceptable surface characteristics while reducing microbial adhesion (Wang et al., 2011; Teimoorian et al., 2023; Moreira et al., 2024). Nevertheless, morphology, dispersion, and polishing can alter both antibacterial exposure and plaque-retentive surface properties, so these variables should be evaluated together.

Graphene-based materials remain primarily at the in vitro proof-of-concept stage. Their antimicrobial effects depend on surface contact and, in some formulations, oxidative mechanisms, while cytotoxicity varies with dose and surface functionalization (Wang et al., 2011; Gholami et al., 2020; Wu et al., 2020). Evidence for activity after salivary pellicle formation, selectivity among oral Gram-positive species, and direct anticaries efficacy remains limited; these gaps currently constrain translational interpretation.

Zwitterionic polymers

Zwitterionic polymers contain no bactericidal payload. Although these hydrophilic materials carry both positive and negative charges within the same molecular structure, they are electrically neutral overall. Their potential for caries prevention therefore depends on preventing bacterial attachment rather than killing bacteria after attachment (Ramburrun et al., 2021). The two most widely studied zwitterionic polymers are 2-methacryloyloxyethyl phosphorylcholine (MPC) and sulfobetaine methacrylate (SBMA), with carboxybetaine-based polymers representing a third, less extensively studied family (Mangal et al., 2020). Because this is fundamentally an antifouling rather than bactericidal strategy, reductions in colony-forming units (CFUs) reported below primarily reflect reduced bacterial attachment, not increased bacterial killing.

Antifouling mechanisms and caries-relevant antibiofilm evidence

The antifouling effect arises from a strongly hydrated layer at the material surface. The closely associated positive and negative charges organize water molecules and create an energetic barrier to protein adsorption, thereby limiting salivary pellicle formation before bacteria can attach (Mangal et al., 2020). An MPC-containing dental bonding agent reduced salivary protein adsorption by 95% and biofilm CFUs by four orders of magnitude compared with the control, while maintaining dentin bond strength (Zhang et al., 2014). Combining MPC with dimethylaminohexadecyl methacrylate (DMAHDM), a quaternary ammonium methacrylate, in a single resin composite couples protein repellency with contact-dependent killing. This combination is potentially advantageous because adsorbed proteins can shield bacteria from the surface and reduce the effectiveness of contact-active quaternary ammonium compounds. However, the proposed synergy has been demonstrated only in vitro and has not been evaluated against an aged, enzymatically remodeled salivary pellicle (Zhang et al., 2015; Torres and Bienek, 2020).

Carboxybetaine represents a third approach in which the antifouling chemistry is applied directly to tooth surfaces rather than incorporated into a polymerizable restorative matrix. A poly(carboxybetaine) polymer conjugated to catechol-based anchoring groups inhibited oral biofilm formation on both hydroxyapatite and human enamel without requiring polymerization (Sun et al., 2021).

Zwitterionic polymers have been incorporated into adhesives, composites, orthodontic materials, sealants, and denture resins, where they reduce protein adsorption and microbial attachment rather than directly kill bacteria (Zhang et al., 2015; Lee et al., 2020; Torres and Bienek, 2020; Kwon et al., 2021; Sun et al., 2021; Wu et al., 2023). Human studies reported reduced plaque accumulation or bacterial counts (Ikeya et al., 2018; Fujiwara et al., 2019), but these remain surrogate outcomes rather than evidence of reduced caries incidence. Formulation-specific results are summarized in Table 6.

Table 6. Antifouling and antibiofilm evidence for zwitterionic polymers in caries-relevant applications.

Clinical evidence for this class includes two independent human studies, which distinguishes zwitterionic polymers from most other material classes considered in this review. An MPC-polymer coating applied to complete dentures reduced plaque accumulation compared with uncoated controls, providing direct evidence that the antifouling effect can operate under intraoral conditions (Ikeya et al., 2018). In a separate study, an MPC-containing mouth rinse reduced bacterial accumulation over several hours compared with the control, although the outcome was bacterial burden rather than a caries-related clinical endpoint (Fujiwara et al., 2019). These findings therefore provide proof of concept for intraoral antifouling activity but do not establish that zwitterionic polymers reduce caries incidence.

Zwitterionic polymers also inhibit C. albicans through the same antifouling mechanism rather than through a distinct antifungal pathway. In several in vitro studies, MPC-containing denture-base resins and coatings reduced or prevented C. albicans biofilm formation compared with untreated and fluorinated controls (Masotti et al., 2020; Bajunaid et al., 2021; Putra Wigianto et al., 2023).

Evidence summary

The caries-relevant antifouling and antibiofilm evidence for zwitterionic polymers discussed above is summarized in Table 6.

Zwitterionic polymers are mechanistically distinct because their principal function is antifouling rather than direct killing. Human studies have demonstrated reductions in plaque-related or bacterial outcomes, but not caries-specific endpoints (Ikeya et al., 2018; Fujiwara et al., 2019). Their favorable biocompatibility profile is encouraging, although oral dose-response data remain limited, and combination systems such as MPC-DMAHDM inherit safety considerations from the bactericidal component (Zhang et al., 2015; Mangal et al., 2020). The strong reduction in salivary protein adsorption reported for MPC-containing materials supports the rationale for this approach in the pellicle-rich oral environment (Zhang et al., 2014).

Biomimetic nanozymes

Cariogenic biofilms are embedded within an extracellular polysaccharide (EPS) matrix that restricts molecular diffusion. This matrix can shield S. mutans from antimicrobial agents and confine acid production within localized microenvironments that are not readily accessible to mechanical plaque removal or fluoride-based therapies (Xu et al., 2025). Biomimetic nanozymes are engineered nanomaterials that mimic enzyme-like catalytic activity, including peroxidase-, oxidase-, catalase-, and superoxide dismutase-like functions (Liu et al., 2024). Their distinguishing feature is the ability of some formulations to become preferentially active within the biofilm microenvironment. For example, iron oxide catalytic nanoparticles (CAT-NP), in the presence of hydrogen peroxide, use peroxidase-like activity to degrade EPS and kill bacteria within acidic biofilm microenvironments (Gao et al., 2016).

Mechanisms and caries-relevant antimicrobial evidence

Peroxidase-like catalysis is the principal mechanism underlying the iron oxide platform. Under the acidic conditions of cariogenic biofilms, iron oxide nanoparticles catalyze the conversion of hydrogen peroxide into ROS, thereby promoting bacterial killing while simultaneously degrading the surrounding EPS matrix (Gao et al., 2016). A dextran-coated iron-oxide (Fe₃O₄) nanozyme (Dex-NZM) further enhances biofilm localization (Naha et al., 2019). Selectivity can be increased by combining glucose oxidase with dextran-coated iron oxide nanoparticles (Dex-IONP-GOx). This system generates hydrogen peroxide from glucose within the biofilm and subsequently converts it to ROS, suppressing S. mutans while sparing the commensal species S. oralis. The reported selectivity reflects both dextran-mediated binding to S. mutans-associated glucan-binding proteins and the lower ROS tolerance of the pathogen relative to the commensal species (Huang et al., 2021).

The same general principle has been explored in several other systems. These include a magnetic cobalt-platinum-graphene nanohybrid (Dong et al., 2022), a system that uses hydrogen peroxide generated by the commensal species S. gordonii (Wang et al., 2020), and an ultrasound-responsive platform in which ultrasound promotes peroxide release, followed by Fenton chemistry that generates hydroxyl radicals (Guo et al., 2023). Cerium oxide nanozymes operate through a different mechanism, using Ce³⁺/Ce⁴⁺ redox cycling to scavenge ROS rather than generate them, particularly under physiological pH conditions (Dhall and Self, 2018).

The original CAT-NP study demonstrated both antibacterial activity and EPS degradation, with bacterial killing and matrix disruption occurring at the same biofilm sites (Gao et al., 2016). A major translational step was the use of ferumoxytol, an iron oxide nanoparticle already approved by the U.S. Food and Drug Administration (FDA) for intravenous treatment of iron deficiency. In combination with low-concentration hydrogen peroxide, ferumoxytol disrupted biofilm architecture and killed embedded bacteria. Subsequent topical administration reduced severe cavitated lesions in vivo without detectable changes in microbiota diversity or injury to gingival or mucosal tissues (Liu et al., 2018).

A subsequent randomized crossover human in situ study provided evidence that the platform can suppress S. mutans-rich biofilms under intraoral conditions. Ferumoxytol combined with hydrogen peroxide preferentially bound to and suppressed S. mutans-rich biofilms relative to commensal streptococci. Its peroxidase-like catalytic activity also provided a visual readout of pathogenic biofilm sites. The reported selectivity was attributed not only to the acidic, peroxide-generating biofilm microenvironment but also to direct recognition of the dextran coating by glucan-binding proteins associated with S. mutans (Liu et al., 2021). The hydrogen peroxide concentrations evaluated in these studies overlap with those used in some commercial oral products (Liu et al., 2018). However, this concentration overlap alone does not establish the safety of repeated topical use in combination with a catalytic nanozyme, which may alter the magnitude and localization of ROS generation.

A more recent development combines Fe₃O₄ nanozymes with stannous fluoride (SnF₂), with the two components providing complementary effects. The combination produced more than a 5-log reduction in viable S. mutans, promoted deposition of a protective iron-tin-fluoride layer on enamel, and prevented cavitation in vivo at an SnF₂ dose fourfold lower than that required for SnF₂ alone (Huang et al., 2023). A structurally distinct silver-graphdiyne ointment uses another approach: under acidic plaque conditions, it converts low concentrations of hydrogen peroxide into hydroxyl radicals while simultaneously releasing Ag⁺ ions. The formulation also promotes salivary calcium and phosphate deposition, thereby supporting hydroxyapatite formation (Liao et al., 2024).

The selectivity observed with Dex-IONP-GOx also translated into reduced disease severity in vivo. Topical treatment significantly reduced caries severity across all lesion categories compared with control treatment or either component alone and was more effective than chlorhexidine for the most severe, fully cavitated lesions (Huang et al., 2021).

Evidence that iron oxide nanozymes directly inhibit C. albicans remains limited. To date, it consists primarily of a supplementary finding from the ferumoxytol rodent study (Liu et al., 2018) and a significant reduction in C. albicans CFU reported for a separate peroxidase-mimicking cobalt ferrite–graphene oxide nanozyme (Ghaffari et al., 2026). The most comprehensive antifungal evidence comes from a different approach in which chitosan-coated iron oxide nanoparticles served solely as drug-delivery carriers for conventional antifungal agents rather than relying on intrinsic nanozyme activity (Caldeirão et al., 2021).

Evidence summary

Table 7 summarizes the antibacterial and antifungal evidence discussed above and indicates whether the available C. albicans evidence is direct, preliminary, or derived from a mechanistically distinct, delivery-based system.

Table 7. Antibacterial and antifungal evidence for biomimetic nanozymes in caries-relevant applications.

Several questions remain unresolved. It is not yet clear whether the pathogen-selective activity demonstrated against bacteria extends to C. albicans with comparable evidence. Independent replication is also needed, particularly because much of the available evidence comes from a limited number of research groups. Finally, whether this approach can be incorporated into a durable delivery format suitable for longer intraoral exposure, rather than short-contact topical application, remains to be determined.

Nanozymes provide microenvironment-responsive catalytic activity and therefore represent one of the more mechanistically distinctive classes reviewed. Ferumoxytol-based systems have reached randomized in situ evaluation of biofilm suppression, but not a direct clinical caries endpoint (Liu et al., 2021). Reported host tolerance is encouraging, yet intravenous approval of ferumoxytol does not establish topical oral safety, and broader independent validation of oral formulations remains necessary (Gao et al., 2016; Liu et al., 2018; Liu et al., 2021).

Antimicrobial peptides: C16G2 and other caries-relevant peptides

Antimicrobial peptides typically act through membrane disruption, although caries-directed designs increasingly add pathogen-targeting or virulence-modulating functions (Ying et al., 2023). C16G2 is antimicrobial peptide that couples an S. mutans-targeting domain to a broad-spectrum killing domain, thereby concentrating membrane-disruptive activity on the target organism (Eckert et al., 2006b; Eckert et al., 2006a; He et al., 2010; Li et al., 2010; Kaplan et al., 2011; Eckert et al., 2012).

Beyond C16G2, representative peptides illustrate broader design strategies. GH12 suppresses S. mutans growth, biofilm formation, acidogenicity, aciduricity, EPS-associated virulence, multispecies biofilms, and caries in an animal model (Wang et al., 2017; Jiang et al., 2018; Wang Y. et al., 2018; Jiang et al., 2020). GA-C16G2 extends the C16G2 scaffold through gallic-acid conjugation (Fu et al., 2025); P-113-DPS suppresses S. mutans cariogenic virulence (Liu et al., 2025); PMF was designed for selective antibacterial and antibiofilm activity against S. mutans (Wei et al., 2026); and ZXR-2 provides additional in vitro activity against caries-associated bacteria (Chen L. et al., 2017).

Together, these studies show a shift toward pathogen-targeted, virulence-modulating, and ecologically informed peptide designs (Jiang et al., 2026). Most non-C16G2 candidates remain preclinical, with proteolytic stability, microbial selectivity, host-cell safety, manufacturing cost, and standardized clinical evaluation remaining key barriers (Jiang et al., 2026).

Mechanism and caries-relevant preclinical and clinical evidence

C16G2 is more potent against S. mutans than its isolated killing domain and shows marked selectivity over S. gordonii and S. sanguinis, indicating that specificity is conferred by the targeting domain (Eckert et al., 2006a). In saliva-derived mixed-species biofilms, it rapidly eliminated S. mutans with little measurable effect on these commensals (Eckert et al., 2006a).

C16G2 kills through selective membrane depolarization and disruption, producing rapid reductions in S. mutans while largely sparing non-target streptococci (Kaplan et al., 2011). Repeated sub-inhibitory passage did not increase its minimum inhibitory concentration (MIC), and pretreatment reduced subsequent S. mutans recolonization (He et al., 2010; Li et al., 2010), although these findings require independent replication.

The only peer-reviewed clinical publication is a pilot study in which a 0.04% mouth rinse reduced plaque and salivary S. mutans, lactic acid production, and enamel demineralization with little change in total plaque bacteria (Sullivan et al., 2011; ClinicalTrials.gov, 2022a). The abstract does not report sample size, effect sizes, or p-values, limiting quantitative interpretation.

C16G2 subsequently entered four registered Phase 2 trials evaluating varnish, strip, combination regimens, or gel; three posted results in 2022 and one has not reported results (ClinicalTrials.gov, [[NoYear]]; ClinicalTrials.gov, 2022a; ClinicalTrials.gov, 2022b; ClinicalTrials.gov, 2022c). In the completed trials, changes in salivary or plaque S. mutans were comparable to or smaller than placebo, without formal statistical comparisons for the primary microbiological endpoint (ClinicalTrials.gov, 2022a; ClinicalTrials.gov, 2022b; ClinicalTrials.gov, 2022c). Details are summarized in Table 8.

Table 8. Representative antibacterial, antibiofilm, and clinical evidence for C16G2 and other caries-relevant antimicrobial peptides.

* GA-C16G2, Gallic acid-C16G2; STAMP, specifically targeted antimicrobial peptide; MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration.

These small exploratory dose-finding studies did not establish a clear, statistically supported dose-response advantage over placebo, but they were not definitive efficacy trials. The appropriate interpretation is therefore failure to establish efficacy, rather than evidence that C16G2 is ineffective.

The corresponding sample-size and formulation details are summarized in Table 8.

Evidence summary

Table 8 summarizes representative mechanistic, preclinical, and clinical evidence for C16G2 and other caries-relevant antimicrobial peptides.

Among the peptides reviewed, C16G2 has the most advanced human evidence, although completed Phase 2 studies did not establish a clear advantage over placebo (ClinicalTrials.gov, [[NoYear]]; Sullivan et al., 2011; ClinicalTrials.gov, 2022a; ClinicalTrials.gov, 2022b; ClinicalTrials.gov, 2022c; Namburu et al., 2022). GH12 has a broader preclinical chain spanning virulence, multispecies biofilms, plaque ecology, and animal caries outcomes (Wang et al., 2017; Jiang et al., 2018; Wang Y. et al., 2018; Jiang et al., 2020), whereas GA-C16G2, P-113-DPS, PMF, and ZXR-2 remain primarily laboratory-supported (Chen L. et al., 2017; Fu et al., 2025; Liu et al., 2025; Wei et al., 2026). Clinical anticaries efficacy beyond C16G2 remains unestablished (Jiang et al., 2026), and no published study has assessed C16G2 compatibility with restorative materials.

Despite being the most clinically advanced peptide reviewed, C16G2 has not demonstrated clinical anticaries efficacy, and the remaining peptide candidates are predominantly preclinical. Future development should prioritize ecological selectivity, oral stability, host safety, durable delivery, and clinically meaningful caries endpoints (ClinicalTrials.gov, [[NoYear]]; Eckert et al., 2006a; Sullivan et al., 2011; ClinicalTrials.gov, 2022a; ClinicalTrials.gov, 2022b; ClinicalTrials.gov, 2022c; Fu et al., 2025; Jiang et al., 2026).

Additional strategies outside the seven-class framework

Four additional strategies merit brief mention outside the seven-class framework. Bioactive glass releases mineral ions, raises local pH, and promotes remineralization; its antibacterial activity against aciduric organisms such as S. mutans appears secondary to alkalinization, and the clinical contribution of antimicrobial versus mineral effects remains difficult to separate (Waltimo et al., 2007; Dai et al., 2019; Skallevold et al., 2019). pH-responsive polymeric carriers can preferentially release agents such as farnesol under cariogenic acidic conditions and have reduced biofilm virulence in a rodent model, but human and restorative-material evidence is lacking (Horev et al., 2015; He et al., 2023). Covalently bound organoselenium can generate superoxide through thiol oxidation and has inhibited bacterial or C. albicans biofilms in dental materials, including clinical evaluations around sealants and orthodontic brackets; long-term caries-outcome evidence remains limited (Kramer and Ames, 1988; Chaudiere et al., 1992; Seko and Imura, 1997; Tran et al., 2013; Tran et al., 2014; Amaechi et al., 2018; Amaechi et al., 2019b; Amaechi et al., 2021; AlMojel et al., 2023; Alawadi et al., 2024). CRISPR-based antimicrobials add sequence-level precision: S. mutans glucosyltransferase editing reduced EPS and biofilm formation, Cas13a established sequence-specific bacterial killing, and nanoparticles have been proposed as delivery carriers (Gong et al., 2018; Kiga et al., 2020; Saffari Natanzi et al., 2025). Most recently, a probiotic-vesicle CRISPR platform targeting gtfB combined S. mutans suppression, reduced biofilm/caries severity, and microbiome modulation in a preclinical model (Zhou et al., 2026). Delivery, off-target effects, carrier reproducibility, host responses, and regulation remain major translational barriers.

Where the evidence base runs thin

Across the seven classes, recurring limitations include heterogeneous outcome measures, limited clinical translation, concentration of evidence within a small number of research groups, and formulation-dependent trade-offs between antimicrobial activity and material performance.

Claims of selectivity are often supported by narrow organism panels. Graphene studies focus predominantly on S. mutans, with little commensal comparison and no basis for inferring selectivity among clinically relevant Gram-positive streptococci from peptidoglycan thickness alone (Pulingam et al., 2019). Gold-titanate selectivity has not been tested in intact multispecies biofilms (Huang et al., 2022). Nanozyme antifungal evidence is preliminary or formulation-specific, and cerium-oxide relevance to caries remains indirect (Dhall and Self, 2018; Liu et al., 2018; Caldeirão et al., 2021; Zhang et al., 2024; Ghaffari et al., 2026). For zwitterionic polymers, reduced CFU may reflect impaired attachment rather than killing; intraoral testing of proposed zwitterionic-QAC combinations and durability evidence also remain limited (Torres and Bienek, 2020; Putra Wigianto et al., 2023).

Clinical endpoints are another major gap. Human zwitterionic studies measured plaque or bacterial outcomes rather than caries (Ikeya et al., 2018; Fujiwara et al., 2019), whereas randomized nano silver fluoride trials directly evaluated caries arrest (Nagireddy et al., 2019; Quritum et al., 2024). A broad systematic review found no established clinical anticaries efficacy for restorative-incorporated antimicrobial materials (do Amaral et al., 2016). C16G2 illustrates the converse problem: despite extensive clinical development, completed Phase 2 microbiological outcomes were modest and lacked formal statistical comparisons, with no conventional animal caries model or clinical caries-incidence trial reported (ClinicalTrials.gov, [[NoYear]]; Armata Pharmaceuticals I, 2020; ClinicalTrials.gov, 2022a; ClinicalTrials.gov, 2022b; ClinicalTrials.gov, 2022c; Fu et al., 2025). Thus, human testing based only on plaque or bacterial endpoints should not be equated with demonstrated anticaries efficacy.

Overall, antimicrobial findings remain much more common than direct anticaries outcomes (do Amaral et al., 2016). Methodological heterogeneity further limits comparison; ISO 3990:2023 standardizes antibacterial testing for several dental material categories but does not establish clinical caries prevention (International Organization for Standardization, 2023). Multifunctional combinations should therefore be tested with standardized methods and clinically relevant endpoints (Melo et al., 2023).

Table 9 provides a concise cross-class comparison of predominant mechanism, trigger, furthest translational stage, compatibility cost, and esthetic risk. Translational stage is classified by the endpoint actually measured, distinguishing microbiological human studies from caries-specific trials.

Table 9. Cross-class comparison of the seven antimicrobial material classes surveyed in this review.

Conclusion

No single class reviewed here resolves the competing demands of antimicrobial activity, material compatibility, safety, ecological selectivity, and clinical caries prevention. QACs and metallic nanoparticles have comparatively mature restorative-incorporation evidence, whereas photocatalytic TiO₂ and nanozymes offer triggered catalytic mechanisms but remain constrained by activation conditions and limited independent validation. Zwitterionic polymers emphasize antifouling rather than killing, graphene remains largely preclinical, and antimicrobial peptides illustrate the potential and difficulty of species-targeted approaches. C16G2 progressed furthest clinically, yet its completed Phase 2 program did not establish a clear advantage over placebo, and no subsequent late-stage clinical development was identified in the literature reviewed (ClinicalTrials.gov, [[NoYear]]; Sullivan et al., 2011; Armata Pharmaceuticals I, 2020; ClinicalTrials.gov, 2022a; ClinicalTrials.gov, 2022b; ClinicalTrials.gov, 2022c; Fu et al., 2025). Across classes, microbiological suppression remains far better documented than reduced demineralization, lesion progression, or caries incidence. Future translation therefore requires clinically relevant anticaries endpoints and formulation-specific therapeutic windows that demonstrate antimicrobial benefit at exposures below unacceptable host toxicity; for several classes, especially QACs and metallic nanoparticles, current efficacy and cytotoxicity datasets are too heterogeneous to define that margin reliably (Tabari et al., 2017; Szymczak-Pajor et al., 2025).

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Footnotes

Edited by: Keke Zhang, Wenzhou Medical University, China

Reviewed by: Panpan Wang, Sun Yat-sen University, China

Tao Gong, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, China