Introduction

Oral cancer, a critical subtype of head and neck malignancy, has emerged as one of the most prevalent malignant tumors worldwide. Among these cases, oral squamous cell carcinoma (OSCC) accounts for over 90% of the total.1 Epidemiological data reveal that global deaths attributed to oral cancer exceeded 170,000 in 2020, imposing an extremely heavy disease burden.2 The high mortality is largely associated with delayed diagnosis. The concealment of early clinical symptoms of oral cancer, coupled with inadequate public awareness of the disease, contributes to this widespread diagnostic delay.3 Clinical statistics indicate that more than 50% of patients are diagnosed at an advanced stage, directly leading to a poor prognosis in which the five-year survival rate remains only around 40%.4 Currently, oral potentially malignant disorders (OPMDs), tobacco exposure, alcohol consumption, betel nut chewing, and human papillomavirus (HPV) infection are recognized as the primary risk factors for oral cancer (Figure 1).1 In clinical practice, the diagnosis of oral cancer remains primarily reliant on oral mucosa macroscopic observation, tissue biopsy, and conventional imaging examinations (eg, CT, MRI, fluorescence imaging).5,6 However, these diagnostic methods exhibit significant limitations: naked-eye observation strongly depends on the clinician’s experience and is therefore subjective; tissue biopsy, while accurate, is invasive and reduces patient compliance; and conventional imaging is constrained by limited resolution, while the potential toxicity of contrast agents remains unresolved.4,5,7 Surgical resection, radiotherapy, and chemotherapy remain the mainstay of treatment.8 Nevertheless, each approach carries clear drawbacks. Surgical resection may result in disfigurement and functional impairments in speech and taste.9 Although radiotherapy and chemotherapy can exert certain therapeutic effects, damage to normal tissues is inevitable and may even induce long-term complications such as cardiovascular diseases.10 Additionally, the presence of biological challenges including multidrug resistance (MDR), abnormal tumor microenvironment, and immune escape further diminishes the therapeutic efficacy in oral cancer.11–13 Therefore, the development of minimally traumatic precision diagnostic and therapeutic strategies with early detection capabilities, precise delivery properties, and multimodal treatment functions has become an urgent need in the field of oral cancer research.14,15 This approach seeks to minimize harm in both the diagnostic and therapeutic processes, ensuring less invasive and more patient-friendly solutions.

Figure 1 Multifactorial risk factors for OSCC and oral potentially malignant disorders (OPMDs). The diagram illustrates interconnected contributors: environmental (eg, alcohol, smoking, betel nut, dust, polycyclic aromatic hydrocarbons [PAH], tobacco-specific nitrosamines [TSNA]); dietary and immune factors; genetic traits (eg, RUNX2); human papillomavirus (HPV) infection; gender; reactive oxygen species (ROS)-mediated cellular damage; and social determinants (eg, healthcare access, community awareness). These elements collectively drive malignant transformation of oral epithelium. Reproduced from,1 Copyright © 2023 by the authors.

The rapid development of nanomaterials has opened up a novel avenue for addressing the clinical challenges in oral cancer diagnosis and therapy. Nanomaterials, with their unique physicochemical properties, such as tunable size, high specific surface area, facile surface functionalization, and excellent biocompatibility, offer promising solutions to overcome the limitations of current imaging and drug delivery systems.16–19 These properties enable nanomaterials to significantly enhance both diagnostic and therapeutic approaches in oral cancer management. For instance, nanomaterials can integrate multimodal imaging agents, thus significantly enhancing diagnostic resolution and specificity, allowing for early and accurate detection of oral cancer.20,21 Furthermore, nanomaterials can be utilized to construct ultrasensitive detection platforms for salivary or serum tumor markers, facilitating non-invasive diagnosis and overcoming the drawbacks of invasive traditional diagnostic methods.22 In addition, nanomaterials can be engineered into targeted, stimulus-responsive drug delivery systems, allowing for real-time control of drug release. This precise, controllable drug delivery addresses the inefficiencies of conventional systems, ensuring targeted and effective therapeutic outcomes while minimizing systemic side effects.16–18,23 Nanomaterial-based theranostic platforms have the potential to synergize with chemotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), gene therapy, and immunotherapy, offering a combined therapeutic effect that enhances the overall efficacy in targeting and treating oral cancer cells.24–26 By integrating multiple treatment modalities, nanomaterials offer a comprehensive approach to overcoming the complex challenges in oral cancer therapy, such as multidrug resistance, tumor heterogeneity, and poor therapeutic targeting.14,27

Despite the increasing in-depth research on nanomaterials in the field of cancer diagnosis and treatment, studies on their applications in OSCC remain fragmented, and their clinical translation process is constrained by multiple factors.28 These include challenges in biosafety assessment, limitations in large-scale production technologies, ambiguity in regulatory classification standards, and the lack of experimental models that accurately recapitulate the human oral microenvironment.29,30 Existing literature predominantly focuses on single dimensions of diagnosis or treatment, lacking a comprehensive and cross-disciplinary systematic summary tailored to OSCC.31 Concurrently, the interaction mechanisms between key design parameters of nanomaterials (such as size, morphology, and surface chemical properties) and OSCC-specific microenvironmental barriers have not been systematically elaborated.32 In view of these unmet needs, this review comprehensively summarizes the latest research progress and application strategies of nanomaterials in OSCC diagnosis and treatment, with a focus on their core role in theranostic integration. To streamline the discussion, we organize the content by key applications and mechanisms: diagnosis (including imaging enhancement and biosensing platforms), targeted delivery systems, and multimodal synergistic therapies (encompassing PTT, PDT, gene/immunotherapy, and combinations). This structure highlights nanomaterial functionalities across diverse platforms while avoiding redundancy in material-specific descriptions The content covers key areas such as nanomaterial-based imaging enhancement systems, biosensor platforms, targeted and stimulus-responsive delivery systems, and multimodal combination therapies. Finally, this paper discusses the clinical translation challenges of nanomaterials in OSCC diagnosis and treatment and proposes future research directions, aiming to provide a scientific basis and development pathway for the design of nanomaterial-based precision theragnostic platforms for OSCC.

Classification of Nanomaterials in Oral Cancer

In the clinical practice of oral cancer diagnosis and treatment, the traditional model is confronted with multiple practical dilemmas.33 First, the accuracy of early screening remains insufficient, hindering timely detection and diagnosis of the disease.34 Second, invasive examination methods, characterized by low patient acceptance, restrict the smooth implementation of clinical diagnosis.35 In the context of treatment, the efficacy of existing therapeutic regimens is limited by factors such as tumor heterogeneity and multidrug resistance, while their significant toxicity and side effects further compromise patients’ quality of life.36 Therefore, breaking through the technical bottlenecks of the traditional diagnosis and treatment model has become a key problem to be addressed in clinical practice.

Endowed with unique physicochemical properties (such as the quantum size effect and surface effect) and excellent biological function-regulating capabilities, nanomaterials offer novel strategies and technical support for overcoming the aforementioned clinical challenges.37,38 They not only compensate for the inherent limitations of conventional diagnostic and therapeutic methods but also open promising research avenues for establishing a precision theragnostic system tailored to oral cancer. The following section will outline the categories and application characteristics of nanomaterials commonly utilized in the field of oral cancer diagnosis and treatment.

Gold Nanomaterials

Owing to their unique optical and physicochemical properties, especially, gold nanomaterials have demonstrated significant application advantages in the field of oral cancer diagnosis and treatment.39 The high specific surface area of gold nanoparticles enables the enhancement of the surface plasmon resonance (SPR) effect.40 Meanwhile, their inherent non-immunogenic characteristics confers low biological toxicity.41 In addition, gold nanomaterials possess excellent ductility, allowing the acquisition of diverse morphological features through the regulation and control of preparation processes. Importantly, morphological variations lead to distinct physicochemical behaviors: for example, the catalytic efficiency of gold nanorods surpasses that of spherical nanoparticles, whereas gold nanocubes demonstrate enhanced bactericidal effects. These observations suggest that particle geometry directly modulates surface atom exposure and binding capacity, and such structure–function correlations are essential for rational design in diagnostic applications.41,42

In terms of diagnostic applications, surface-enhanced raman scattering (SERS) technology leverages the robust SPR effect of gold nanoparticles to achieve efficient enhancement of Raman scattering signals, thereby significantly improving the sensitivity of tumor detection.41 Compared with conventional fluorescent probes, SERS provides higher photostability and signal specificity; however, the reproducibility of “hot spot” generation at the molecular level remains a major technical challenge. Given the challenges in early detection and surgical margin determination posed by the irregular anatomical structure of the oral cavity, the SPR properties of gold nanomaterials can enhance the contrast of oral imaging, leading to a marked improvement in diagnostic accuracy.43 David et al successfully sorted and identified 12–17% of tumor cells by constructing a gold-coated magnetic nanoparticle system and combining magnetic sorting with SERS technology for the detection of colorectal cancer tumor cells. This study confirmed that the integration of gold nanoparticles, magnetic nanomaterials, and SERS technology can effectively enhance the sensitivity of tumor detection.44 This integration illustrates a synergistic mechanism: magnetic nanomaterials enable efficient physical enrichment of tumor cells, while gold nanomaterials amplify Raman signals at the molecular level, together producing higher diagnostic sensitivity. However, the approach requires further validation in oral cancer models, and issues such as probe stability, background interference, and large-scale clinical applicability remain unresolved.44

As an emerging imaging technology, diffuse reflectance spectroscopy (DR) enables tumor diagnosis by identifying the specific optical characteristics of tissues across different wavelengths.40 Endowed with unique optical properties, gold nanoparticles can be selectively enriched in tumor tissues, thereby altering their optical profiles and enhancing the diagnostic sensitivity of DR technology.40 For example, Sudri et al confirmed that after anti-epidermal growth factor receptor (EGFR) monoclonal antibody-coupled gold nanorods specifically bound to EGFR on the surface of tumor tissues, DR detection revealed a marked enhancement of optical signals in OSCC model rats.45 This study underscores the importance of molecular targeting: antibody conjugation ensures selective nanoparticle accumulation at tumor sites, while anisotropic nanorods amplify optical responses through shape-dependent SPR effects. Compared with untargeted nanoparticles, such active targeting strategies improve tumor-to-normal tissue contrast. Nevertheless, practical challenges—including antibody stability, immunogenic risk, and the high cost of bioconjugation—may hinder widespread clinical translation. Overall, these findings indicate that diagnostic strategies based on the optical properties of gold nanomaterials hold great promise for the early and accurate detection of oral cancer.40,46

In the field of therapeutic applications, gold nanoparticles can efficiently achieve the conversion of light energy to thermal energy under near-infrared (NIR) light irradiation. By generating local hyperthermia in tumor tissues, they exert a photothermal therapeutic effect, enabling the selective killing of tumor cells.47 Meanwhile, due to their excellent biocompatibility and surface modifiability, gold nanoparticles are frequently engineered as drug delivery carriers.48 In particular, surface functionalization enhances their targeted delivery capability by enabling specific binding to tumor-associated receptors or microenvironmental cues. Khamaikawin et al demonstrated that when gold nanoparticles loaded with docetaxel, cisplatin, and fluorouracil were applied in the treatment of head and neck squamous cell carcinoma models, the system achieved precise targeted drug delivery and efficient intracellular accumulation, while maintaining therapeutic efficacy with reduced doses of chemotherapeutic drugs.49 This not only highlights their potential to minimize systemic toxicity but also underscores the synergistic advantage of combining photothermal properties with controlled drug release.

While gold nanomaterials excel in exploiting SPR for enhanced imaging and photothermal effects, their molecular interactions with OSCC cells primarily involve receptor-mediated endocytosis via ligands such as anti-EGFR antibodies, which bind to overexpressed EGFR on tumor surfaces (affinity Kd ~10–100 nM).40,45 This interaction facilitates clathrin-dependent uptake and subsequent lysosomal escape, thereby improving intracellular delivery efficiency. In the acidic tumor microenvironment (TME, pH 6.5–6.8), thiolated coatings on AuNPs can protonate, triggering pH-responsive drug release and mitigating hypoxia-induced resistance by enhancing ROS generation.50 Comparative studies show that gold nanorods (AuNRs) outperform spherical AuNPs in NIR absorption (peak at ~800 nm vs 520 nm), achieving 20–30% higher photothermal conversion efficiency (η ~50%).51 However, AuNRs are prone to shape-dependent aggregation in the viscous oral mucosa, which reduces tumor penetration depth by up to 40% compared with magnetic nanomaterials.40 Targeting strategies typically combine active mechanisms (eg, antibody conjugation) with passive accumulation via the enhanced permeability and retention (EPR) effect.52 Yet, the reliability of the EPR effect in OSCC remains controversial, as dense stromal architecture and elevated interstitial pressure restrict nanoparticle extravasation. Despite these advances, several limitations persist. Long-term hepatotoxicity due to Au3⁺ ion leaching has been reported in 15–20% of preclinical models.53 Moreover, early AuNR-PEG clinical attempts failed due to poor clearance kinetics, leading to off-target splenic accumulation and immune activation.54 Recent strategies employing zwitterionic coatings show promise in improving circulation stability and reducing immune recognition, but large-scale GMP validation remains necessary.55,56 Taken together, these insights highlight both the mechanistic advantages and translational challenges of Au-based systems, underscoring the need for hybrid nanoplatforms that balance efficacy and safety in the heterogeneous TME of OSCC.

Magnetic Nanomaterials

Magnetic nanomaterials are primarily composed of magnetic metal elements such as iron, cobalt, nickel, and manganese. By adjusting parameters including the size, morphology, and elemental composition of these nanomaterials, their physicochemical properties can be optimized, thereby enabling them to exert more significant effects in the diagnosis and treatment of oral cancer.57 These materials possess excellent magnetic properties and structural stability, and their biocompatibility can be effectively enhanced through surface coating or ligand functionalization. In addition, some magnetic nanomaterials exhibit controlled biodegradability, with iron oxide nanoparticles (IONPs) serving as a representative example. In this case, Fe2⁺/Fe3⁺ ions can be metabolized through normal iron pathways, thereby reducing long-term toxicity.58,59

As one of the most widely utilized magnetic nanomaterials, IONPs can serve as contrast agents for MRI in diagnostic applications. By shortening the relaxation time of water molecules, tumor tissues enriched with magnetic nanoparticles exhibit a significantly low signal in T2-weighted imaging, thereby enabling precise tumor localization and diagnosis.60 Montiel et al confirmed that folic acid-modified IONPs, when used for MRI detection, can specifically target ovarian cancer cells with overexpressed folic acid receptors and successfully achieve targeted imaging of ovarian cancer.59 This finding highlights the importance of molecular interactions between targeting ligands and tumor cell receptors, suggesting that receptor-mediated endocytosis plays a critical role in improving imaging specificity. More recently, iron carbide has emerged as a novel magnetic nanomaterial, with magnetization reaching 140 emu/g—significantly higher than that of traditional IONPs—and strong corrosion resistance that enhances stability in physiological environments. Compared with IONPs, iron carbide offers superior magnetic responsiveness and imaging contrast; however, its biocompatibility and biodegradability remain insufficiently validated, raising concerns for long-term clinical application.57

In the field of therapeutic applications, magnetic nanomaterials are frequently engineered as drug delivery carriers. For instance, hyaluronic acid-modified Fe3O4 magnetic nanoparticles can specifically target oral cancer cells with overexpressed CD44, enabling the precise delivery of therapeutic siRNA to oral cancer lesions under the guidance of an external magnetic field.61 In this system, the molecular interaction between hyaluronic acid and CD44 ensures selective binding and internalization, illustrating how passive magnetic targeting can be synergistically combined with active receptor-mediated uptake. In addition, magnetic nanomaterials can generate local hyperthermia under the action of an alternating magnetic field, exerting a hyperthermic effect to kill tumor cells.62 Legge et al demonstrated that when magnetic nanoparticles modified with anti-αVβ6 monoclonal antibodies acted on OSCC cells with high αVβ6 expression, high temperatures could be rapidly generated through alternating magnetic field induction, effectively inducing the death of OSCC cells.63 This strategy exemplifies a dual-targeting mechanism: antibody conjugation improves tumor specificity, while the magnetic field enables spatial control over therapeutic heating. However, limitations—including uneven heat distribution, the risk of off-target thermal damage, and potential immune activation—remain significant challenges that must be addressed prior to clinical translation.

Mechanistically, magnetic nanomaterials such as IONPs interact with OSCC cells through their superparamagnetic properties.64,65 Under external magnetic fields (0.5–2 T), the alignment of Fe3⁺/Fe2⁺ spins shortens T2 relaxation times (r2 > 100 mM⁻1s⁻1), thereby enhancing water proton dephasing and producing high-contrast MRI signals, particularly in hypoxic regions of the TME.66 Targeting is often achieved through folate or hyaluronic acid (HA) ligands binding to CD44 (Kd ~1 nM), which promotes caveolae-mediated endocytosis and facilitates magnetic hyperthermia (SAR > 500 W/g).67 This hyperthermia disrupts mitochondrial membranes and alleviates hypoxia by vasodilating tumor vessels, increasing oxygen perfusion by 25–50%.67,68 In comparative evaluations, IONPs provide superior magnetic guidance for deep-seated oral lesions, whereas gold nanomaterials offer greater optical versatility, achieving 50% photothermal efficiency compared to only 30–40% for IONPs.69 However, limitations remain. Excess Fe2⁺ can trigger Fenton reactions, producing hydroxyl radicals that exacerbate TME inflammation in 20–30% of preclinical models.70 Debates persist regarding biodegradability: although IONPs can degrade into ferritin and be metabolized via normal iron pathways, incomplete clearance within fibrotic OSCC stroma may lead to chronic toxicity.71,72 To address these concerns, Mn-doped IONPs have been explored, which enhance r1/r2 ratios and potentially reduce oxidative stress while improving imaging performance.

Polymer Nanomaterials

Polymer nanomaterials are composed of high-molecular-weight polymers, with a typical particle size range of 1–100 nm. These materials exhibit outstanding characteristics including strong designability, excellent biocompatibility, and favorable targeting capabilities.73 Endowed with these superior physicochemical properties, polymer nanomaterials have garnered widespread attention and favor from researchers in the field of disease diagnosis and treatment. Through regulation of polymerization modes and surface modification, researchers can precisely tailor their physicochemical properties and targeting functions.74 In addition, certain natural polymers (such as hyaluronic acid and albumin) or biodegradable polymers (such as PLGA and PEG) can effectively reduce immune rejection. For instance, aggregation-induced emission (AIE) photosensitizers encapsulated by bovine serum albumin (BSA) nanoparticles can significantly enhance biocompatibility, thereby facilitating preferential accumulation of photosensitizers at tumor sites.73

In the field of medical imaging, polymer nanomaterials are widely applied in MRI. For instance, magnetic PLGA nanoparticles modified with folate-modified chitosan can target and recognize oral cancer cells. By shortening the T2 relaxation time, they significantly enhance the contrast of MRI images, thus improving diagnostic accuracy and providing clinicians with a more reliable basis for treatment planning.38 Polymer nanomaterials are also widely utilized in drug delivery systems. Following surface modification, they can achieve targeted recognition of oral tumor cells and precise drug release. A representative example is the hyperbranched polymer nanoparticles (DOX/HαO-PLA@PDA-PEG-FA NPs) developed by Yin et al, which were surface-modified with polydopamine (PDA) and folic acid.75 These nanomaterials demonstrated strong therapeutic efficacy in oral cancer, as doxorubicin (DOX) loaded onto them selectively targeted folate receptor–overexpressing tumor cells. Meanwhile, PDA provided high photothermal conversion efficiency, enabling synergistic photothermal–chemotherapy to eradicate local tumor cells.76 Furthermore, the degradable components of these nanoparticles (HαO-PLA, PDA, and PEG-FA) effectively reduced systemic toxicity.77

At the molecular level, polymer nanomaterials such as PLGA interact with OSCC cells through amphiphilic self-assembly, where hydrophobic cores encapsulate doxorubicin (DOX) via π–π stacking (loading >20 wt%), while PEG shells sterically hinder protein corona formation, thereby extending systemic circulation (t1/2 >24 h).78 Targeting strategies typically employ FA–HA conjugates that bind folate and CD44 receptors, subsequently triggering hyaluronidase-mediated degradation in the TME (with enzyme levels elevated 5–10×), which enables burst drug release and matrix remodeling to enhance nanoparticle diffusion in the dense collagen stroma.79 In TME interplay, pH-sensitive hydrolysis of PLA ester bonds (at pH <6.8) produces lactic acid, amplifying local acidosis. This effect synergizes with PTT by denaturing HSP70 chaperones, thereby reducing treatment resistance.80,81 Relative to lipid nanomaterials, polymer-based carriers exhibit tunable degradation kinetics (weeks vs hours) but their higher mechanical rigidity restricts endosomal escape (efficiency ~40% vs 70%).82 Despite these advantages, key limitations remain. Heterogeneous degradation generates acidic byproducts that can damage adjacent healthy mucosa, with necrosis observed in 10–15% of xenograft models.83 Furthermore, dendrimer-based systems have faced translational hurdles; for example, a PAMAM trial failed due to cationic toxicity that disrupted oral epithelial barriers.84 Controversies also persist regarding the protein corona effect, which may alter targeting specificity in saliva-rich environments.85 This has prompted exploration of mucoadhesive modifications, such as chitosan grafting, to enhance retention without compromising biocompatibility.

Lipid Nanomaterials

Lipid-based nanoparticles (LBNPs) are a class of nanomaterials with lipids as the main component. Since most of their components are natural lipids or lipid-like substances, they display excellent biocompatibility and biodegradability.86 Through rational design and surface modification, LBNPs can be engineered into diverse forms suitable for oral cancer therapy, including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, microemulsions, lipid–polymer hybrid nanoparticles, self-nanoemulsifying drug delivery systems, and lipid-core nanocapsules (Figure 2).25,87

Figure 2 Overview of lipid-based nanoparticles (LBNPs) for OSCC theranostics. LBNPs encompass a family of colloidal carriers including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, nano-/micro-emulsions, lipid–polymer hybrid nanoparticles, self-emulsifying drug-delivery systems and lipid-core nanocapsules. Liposomes—shown here as a representative subtype—consist of a spherical phospholipid–cholesterol bilayer that forms an aqueous core suitable for hydrophilic drugs while the lipid shell accommodates lipophilic agents, thereby enabling dual encapsulation. Other LBNPs display diverse core–shell architectures in which solid, liquid or nanostructured lipid matrices serve as reservoirs for therapeutic or diagnostic payloads. Surface functionalization with surfactants, PEG chains or targeting ligands further improves stability, biocompatibility and tumor-specific accumulation via the EPR effect and/or receptor-mediated recognition. Reproduced from,87 Copyright © 2024 by the authors.

Among these, liposomes are single-layer or multi-layer spherical structures composed of phospholipids and cholesterol. Their aqueous core can encapsulate hydrophilic drugs, while the lipid bilayer can carry lipophilic drugs.25 Due to their lipid-based composition, liposomes exhibit high biocompatibility and low toxicity, making them particularly attractive for biomedical use.88 This unique structural advantage, combined with favorable stability, underpins their broad application in the diagnosis and treatment of oral cancer. For example, Wei et al prepared liposomes of approximately 120 nm in diameter loaded with evodiamine (Evo), a natural alkaloid, and indocyanine green (ICG), a photosensitizer. Liposomes of this size efficiently exploit the EPR effect to selectively deliver therapeutic cargos to tumor sites.89 While the hydrophobic nature of Evo limits its delivery when used alone, liposome encapsulation significantly improves its aqueous solubility and tumor accumulation. Simultaneously, encapsulated ICG exhibits reduced degradation in systemic circulation, thereby enhancing tumor accumulation and improving imaging precision.90 In addition, liposomes can achieve targeted drug delivery to oral cancer cells through specific modification, thereby reducing damage to normal oral tissues.91 Based on the characteristics of high folate receptor expression in breast cancer cells, Peres-Filho et al developed folate-modified liposomes to encapsulate paclitaxel and imatinib. The results demonstrated that, compared with conventional liposomes, these targeted liposomes significantly increased the mortality of breast cancer cells and reduced the expression of the vascular endothelial growth factor (VEGF) gene, thereby inhibiting tumor cell growth.92 Although direct applications of modified liposomes in oral cancer remain limited, the confirmed overexpression of folate receptors in oral tumor cells provides a strong theoretical basis for targeted liposomal therapy in OSCC.93

Lipid nanomaterials facilitate OSCC targeting through bilayer fluidity, which enables membrane fusion with tumor endosomes via lipid raft incorporation (ΔG ~ –20 kJ/mol).94 At this stage, encapsulated ICG/Evo payloads disrupt the mitochondrial electron transport chain (ETC), increasing ROS generation in the hypoxic TME (O2 <5%).95 Active targeting through folate ligation exploits FRα overexpression, while passive accumulation occurs via the EPR effect in leaky tumor vasculature.96 Within the TME, phospholipase A2 hydrolyzes phosphatidylcholine headgroups, inducing lysosomal leakage and amplifying PDT efficacy by 2–3 fold.52 Compared with polymer carriers, lipid-based systems provide superior biocompatibility (cytotoxicity <5% at 100 μg/mL) but exhibit shorter structural stability under oral shear forces, degrading nearly 50% faster.87 Major limitations include rapid hepatic uptake (clearance t1/2 <2 h) and peroxidation instability in ROS-rich TMEs, which can cause payload leakage of up to 30%.97 These shortcomings were evident in failed liposomal DOX trials, where suboptimal tumor exposure was further compromised by ABC transporter–mediated efflux.98 Controversies also remain regarding the immunogenicity of cationic lipids, as anti-PEG antibodies have been detected in 15–20% of patients, reducing the efficacy of repeated dosing.99 While “stealth” DSPE–PEG coatings can mitigate this effect, they underscore the ongoing need for saliva-compatible formulations tailored to the oral environment.

Quantum Dot

Quantum dots are a class of semiconductor nanocrystals with a diameter ranging from 2 to 10 nm, exhibiting unique optical and electronic properties.100 They are typically composed of binary or ternary alloys from groups II–VI, III–V, and IV–VI in the periodic table.101 Owing to these distinctive optical properties, quantum dots have attracted significant attention for the diagnosis and treatment of oral cancer. For instance, the fluorescence intensity of quantum dots is considerably higher than that of traditional organic dyes, rendering them more sensitive probes in biological imaging applications. In addition, quantum dots are resistant to fluorescence quenching under light irradiation and exhibit excellent optical stability, meeting the requirements of long-term imaging.102 In addition, by adjusting the size of quantum dots, researchers can precisely tune the wavelength of their emitted light can be precisely tuned, thereby enabling multicolor imaging.102 Relevant studies have shown that near-infrared quantum dots with emission wavelengths in the range of 700–900 nm exhibit strong tissue penetration and low in vivo toxicity; meanwhile, quantum dots with emission wavelengths between 400 and 600 nm can effectively avoid interference from tissue autofluorescence, making them suitable for biological imaging scenarios.38 In the research conducted by Yang and Chen, EGFR antibodies were conjugated with QD800, and the high tissue penetration and low in vivo toxicity characteristics of quantum dots within the 700–900 nm range were successfully applied to the diagnosis and imaging of human carcinoma OSCC.58

Quantum dots also exhibit significant advantages in biosensor detection. Wu et al developed a fluorescent magnetic bioprobe based on quantum dots, which integrates the aptamer of the exosome marker CD63, magnetic microspheres (MMS), DNA linkers, and quantum dots for the detection of CD63 on the surface of exosomes secreted by human OSCC CAL27 cells. When the aptamer specifically binds to CD63 on exosomes, the DNA linkers are released and coupled with multiple quantum dots. This design produces a signal amplification effect of “one exosome–multiple quantum dots”, thereby conferring high sensitivity, a low detection limit, and strong anti-interference performance in complex biological matrices. Experimental data show that the detection limit can be as low as 500 particles/μL, with a detection range spanning three orders of magnitude. Moreover, the detection fluorescence intensity in salivary matrices with volume ratios of 25%, 50%, and 75% is comparable to that in buffer solutions.103 These findings provide strong evidence supporting the potential transformation of traditional invasive tissue biopsy into simpler and less invasive liquid biopsy strategies for oral cancer.

In addition, studies have indicated that quantum dots may enhance the antitumor activity of drugs.104 However, despite their great potential in cancer diagnosis and therapy, the toxicity of quantum dots should not be overlooked. For instance, the accumulation of quantum dots in the human body may cause damage to organs such as the heart, kidneys, and liver; meanwhile, light-activated quantum dots may generate ROS, which could induce DNA damage and cell apoptosis.105 Notably, recent studies have found that carbon-based quantum dots exhibit low toxicity, which provides a new research direction for addressing the biosafety issues of quantum dots.106

Quantum dots’ bandgap engineering (via size tuning, 2–10 nm) enables multicolor emission (400–900 nm) through excitonic recombination, interacting with OSCC biomarkers like CD63 via aptamer hybridization (affinity >106 M⁻1), amplifying signals in exosome detection by FRET quenching reversal.105,107 In TME, their ROS scavenging counters phototoxicity, but hypoxia quenches NIR emission by 20–30%, mitigated by O2-generating Mn-doping.108 Targeting merges electrostatic adsorption to sialylated glycans with EPR, yet lags behind gold nanomaterials in thermal synergy (photothermal η <10% vs 50%). Limitations include Cd/Se leaching causing genotoxicity (DNA adducts in 25% models) and failed QD-biosensor trials due to autofluorescence interference, yielding 15% false positives.109 Controversies debate “blinking” artifacts inflating sensitivity claims, favoring carbon QDs for biocompatibility but urging surface passivation to resolve oxidative instability in oral biofilms.110

Application of Nanomaterials in the Diagnosis of Oral Cancer

After outlining the potential of nanomaterials in the diagnosis of oral cancer, we now turn to their specific applications. Nanomaterials not only offer remarkable advantages in imaging enhancement but also enable more sensitive and non-invasive detection methods through biosensing platforms and early diagnostic approaches.111 The application of these technologies is expected to greatly improve the early detection and diagnostic accuracy of oral cancer, thereby providing a stronger foundation for clinical decision-making and potentially serving as a key element in the translational pipeline of nanomaterial-based diagnostics (Figure 3).97,98 In the following section, we will provide a detailed introduction to the various specific applications of nanomaterials in the diagnosis of oral cancer (Table 1).

Figure 3 Translational pipeline of nanomaterials in the diagnosis of oral cancer. Schematic overview of representative nanomaterial-based strategies for oral cancer diagnosis, including optical coherence tomography (OCT), magnetic resonance imaging (MRI), photoacoustic imaging, surface plasmon resonance scattering, surface-enhanced Raman scattering (SERS), diffusion reflection imaging, quantum dot (QDs) imaging, and nano-based ultrasensitive biomarker detection. These nanotechnologies not only provide enhanced imaging contrast and sensitivity but also enable non-invasive and early detection platforms with potential clinical applicability. Advantages (green) and limitations (red) of each technique are summarized. Collectively, these approaches highlight the translational pipeline of nanomaterials from bench to clinic, offering promising opportunities for improving early diagnosis and personalized management of oral cancer. Reproduced from,38 Copyright © 2018 by the authors.

Table 1 The Applications of Nanomaterials in the Diagnosis of Oral Cancer

Imaging Diagnosis

The early diagnosis of oral cancer faces significant challenges. Traditional imaging diagnostic techniques such as computed tomography (CT) and MRI suffer from inherent limitations, including insufficient resolution, low specificity for detecting oral cancer cells, and potential toxicity risks from contrast agents.4,5,7 The integration of nanomaterials with conventional diagnostic technologies provides an effective strategy to overcome these issues. By modifying nanomaterial-based contrast agents with ligands targeting receptors overexpressed on oral cancer cells, specific tumor binding and lesion-site accumulation can be achieved, thereby significantly enhancing imaging resolution.

For example, the folate-modified chitosan/magnetic poly (lactic-co-glycolic acid) (PLGA) nanoparticle contrast agent developed by Shanavas et al can specifically target folate receptors overexpressed on oral cancer cells. This contrast agent accumulates at tumor sites and markedly improves oral cancer imaging by shortening the T2 relaxation time in MRI, achieving 92.3% sensitivity and 92.3% specificity in optical coherence tomography (OCT)-integrated models for early OSCC detection127 Moreover, PLGA as the main component confers good biodegradability, thereby reducing systemic toxicity.128 Nanomaterials can also be engineered into nanoprobes for imaging diagnosis. The gastrin-releasing peptide receptor (GRPR) is an important target for the imaging and treatment of OSCC. Li et al developed a GRPR-specific nanographene oxide (NGO) nanoprobe and applied it to infrared fluorescence imaging of OSCC, which significantly optimized the imaging effect (AUC 0.96) and provided a powerful tool for the accurate diagnosis of OSCC.127 Molecularly, folate-PLGA nanoprobes bind FRα via hydrophobic pockets (Kd ~5 nM), accumulating in TME via EPR and cathepsin B cleavage of PEG linkers, shortening T2 by 50% for MRI contrast while NGO’s π-stacking quenches background fluorescence.129,130 This interplay remodels hypoxic stroma, improving penetration 1.5-fold.131 Multimodal superiority over single-mode CT (resolution <1 mm vs 0.5 mm) is evident, but limitations include off-target liver uptake (40% dose) and failed GRPR-probe trials due to rapid metabolism.132,133 Controversies question TME heterogeneity confounding specificity, necessitating AI-enhanced image analysis.134

Biosensor

A biosensor is a detection device that can specifically interact with target biological molecules (such as proteins, DNA, RNA, etc.) or tumor biomarkers, and convert the resulting biorecognition signals into electrical or optical signals. Tumor diagnosis is achieved through quantitative analysis of the target components.115 Based on the differences in recognition elements, biosensors can be roughly categorized into three types: DNA biosensors, RNA biosensors, and protein biosensors.135 According to their working principles and signal transduction mechanisms, they can also be categorized as electrochemical, optical, photoelectrochemical, and piezoelectric biosensors.136,137

Biosensors exhibit several notable advantages for tumor detection. They possess high sensitivity and specificity, enabling detection of target molecules at extremely low concentrations while effectively distinguishing structurally similar molecules.138 The detection process is non-invasive, relying on saliva or mucosal samples, thereby avoiding the pain associated with conventional tissue biopsies.139 In addition, biosensors can simultaneously detect multiple biomarkers and offer benefits such as portability and low cost, further supporting their clinical applicability.140,141 The integration of nanomaterials with biosensors can further enhance both specificity and sensitivity for oral tumor marker detection. Commonly employed nanomaterials in biosensor construction include metal nanoparticles, carbon-based nanomaterials, metal oxide nanomaterials, and dendrimers.140,142 These nanocomposite-based biosensors not only improve sensitivity but also extend detection to body fluid samples such as saliva, thereby fully realizing the non-invasive diagnostic potential of this technology. For instance, Li et al developed a non-enzymatic electrochemical DNA biosensor based on AuNPs@ZIF-8 nanocomposites, which can be used to detect oral cancer overexpressed 1 (ORAOV1)—the abnormal expression of this gene can serve as a biomarker for the early diagnosis of oral cancer. The detection limit of the sensor is as low as 163 aM, with a sensitivity of 91% and specificity of 81% in salivary biomarker assays.18

Biosensors based on carbon nanomaterials exhibit ultra-high detection sensitivity. The high conductivity and large specific surface area characteristics of carbon nanotubes and graphene can significantly enhance the sensing capability of electrical signals and improve the detection response.115 Ding et al constructed an electrochemical immunosensor using vertically aligned multi-walled carbon nanotubes (VANTA) for the detection of the oral cancer marker CIP2A, with a detection limit as low as 0.24 pg/mL, accuracy of 88.3%, and shorter response time compared to the traditional enzyme-linked immunosorbent assay (ELISA) method.143 Fluorescent immunosensors based on quantum dots demonstrate their application value in the detection of oral tumor markers due to their high fluorescence intensity and ease of surface modification.144 Mercaptopropionic acid-functionalized cadmium telluride quantum dots (CdTe@MPA) can specifically bind to antibodies against the breast cancer marker CA 15–3, enabling the detection of target protein through changes in the fluorescence signal of the quantum dots (sensitivity 88.9%, specificity 75%).145 Similarly, studies have shown that graphene based electrochemical biosensors perform well in detecting oral cancer-related biomarkers. For example, some sensors can achieve a detection limit of 0.13 pg/mL and a dynamic range of 0.01–80 ng/mL when detecting prostate-specific antigen (PSA); When detecting microRNAs (miRNAs), the detection limit of some sensors can be as low as 0.2 fM, with a dynamic range of 10 fM-10 µ M.146 In addition, the introduction of materials such as QDs and AuNPs further enhances the sensitivity and selectivity of the sensor. For example, some electrochemical sensors based on AuNPs can achieve a detection limit of 0.1 fM and a dynamic range of 10 fM-10 nM when detecting microRNAs.146,147 Although biosensors have shown great potential in the diagnosis of oral cancer, there are still some challenges: for example, biological samples such as saliva and blood contain multiple interfering substances that may affect the performance of the sensor, leading to false positive or false negative results.148 In addition, certain sensors may experience signal drift or attenuation during long-term use or in complex samples, which can affect the accuracy of detection results.149 Future research should focus on improving the stability, specificity, and anti-interference ability of sensors. In addition, developing multimodal sensors (such as simultaneously possessing electrochemical, fluorescence, and surface plasmon resonance functions) may help improve the accuracy and reliability of diagnosis.150 Meanwhile, combining artificial intelligence and big data analysis may provide more accurate tools for early screening of oral cancer.151

Application of Nanomaterials in the Treatment of Oral Cancer Nano Drug Delivery System

Nanoparticle drug delivery systems (NDDS) are therapeutic or diagnostic platforms based on nanomaterials, designed to precisely deliver drugs or contrast agents to tumor cells or specific tissues through specialized targeting mechanisms.25 The drug delivery mechanisms of NDDS mainly include passive targeting, active targeting, immune targeting, and magnetic targeting (Figure 4).25 Passive targeting exploits the EPR effect unique to tumor vasculature, allowing nanoparticles to accumulate selectively at tumor sites. Active targeting involves surface modification of nanocarriers with peptides, antibodies, or carbohydrates to achieve specific binding with receptors overexpressed on tumor cell membranes. Magnetic targeting utilizes magnetic nanomaterials such as iron oxide nanoparticles (IONPs), which can be guided to tumors under an external magnetic field. Immune targeting aims to stimulate the immune system by employing tumor-specific vaccines or antibodies to enhance anti-tumor responses (Table 2).25,104,152

Figure 4 Nanoparticle targeting strategies for OSCC. Passive targeting leverages the EPR effect, allowing non-targeted nanoparticles to accumulate in tumor tissues through endothelial discontinuities, while sparing normal tissues with intact barriers. Active targeting employs surface ligands (eg, antibodies, peptides) that bind overexpressed receptors (eg, EGFR, folate receptors) on OSCC cells for precise accumulation. Reproduced from,153 Copyright © 2019 by the authors.

Table 2 Nanomaterials for the Treatment of Oral Cancer

In addition, nanoparticle drug delivery systems can respond to stimulus signals from the tumor microenvironment (such as pH value, enzyme concentration, and redox potential) or external environments (such as light, temperature, ultrasound, magnetic fields, and electric fields) to achieve precise and controllable drug release.172,173 For example, in a siRNA/doxorubicin (DOX) co-delivery system, hollow mesoporous organosilica nanoparticles (HMONs) were capped with poly(β-amino ester) (PAE) via disulfide linkages. Once internalized into tumor cells, elevated intracellular glutathione levels cleaved the disulfide bonds, opening the mesoporous channels of HMONs and triggering the controlled release of DOX.174 Meanwhile, the nanomaterial carriers in nano drug delivery systems can enhance drug loading capacity (eg, 250 μg/mg for DOX in catechin-modified chitosan/hyaluronic acid nanoparticles) and reduce toxicity to normal tissues.175,176 The PEG-citrate dendrimers synthesized by Ebrahimi et al are covalently conjugated with curcumin via ester bonds, which not only improve drug loading capacity (up to 20% w/w) and delivery stability but also endows the nano drug delivery system with extremely low toxicity due to PEG being a biodegradable material.177

Delivery systems based on nanomaterials can also be combined with PTT, PDT gene therapy, and immunotherapy to further enhance therapeutic efficacy.178–181 For example, targeted delivery of silencing genes or tumor vaccines can be achieved by encapsulating mRNA within nanocarriers, thereby improving stability and cellular uptake.182,183 Jang et al developed gold nanorods (AuNRs) modified with aluminum phthalocyanine tetrasulfonate as a surface photosensitizer. In a mouse tumor model, the combination of PTT and PDT achieved a tumor growth inhibition rate of 95%, compared with only 79% when PDT was applied alone, demonstrating the synergistic advantage of multimodal therapy.184

At present, chemotherapy and radiotherapy remain the core approaches for cancer treatment; however, MDR of tumor cells is the primary cause of chemotherapy failure and tumor recurrence.185 The mechanisms of MDR include ATP-binding cassette (ABC) transporter–mediated efflux of chemotherapeutic agents (eg, P-gp, MRP, BCRP), enhanced DNA repair capacity, alterations in the tumor microenvironment, dysregulated apoptotic pathways, and the intrinsic drug resistance of cancer stem cells.185–188 Nano drug delivery systems can effectively overcome chemotherapy resistance in tumors through multiple mechanisms. For instance, Wang et al demonstrated that nanocarrier-mediated delivery of P-gp inhibitors or P-gp-targeted siRNA reduced P-gp expression levels, thereby alleviating tumor drug resistance.189 Similarly, Zhu et al developed HT@ER/PTX nanoparticles that co-loaded the P-gp inhibitor erlotinib (ER) and paclitaxel (PTX) at a 1:1 ratio (encapsulation efficiency >85%). These nanoparticles, surface-modified with hyaluronic acid (HA), targeted CD44 receptors overexpressed in drug-resistant breast cancer cells, facilitating receptor-mediated endocytosis and enhancing intracellular drug accumulation.190

Photothermal and Photodynamic Therapy

Photodynamic therapy (PDT) is a minimally invasive cancer treatment modality. Its mechanism relies on the selective delivery of photosensitizers to tumor sites, where, upon excitation with light of a specific wavelength, the photosensitizers react with oxygen to generate ROS, thereby inducing tumor cell damage.191 PTT, by contrast, employs near-infrared (NIR) light to excite photothermal converters, which convert light energy into heat, increasing the local tumor temperature and ultimately destroying tumor tissues.192

However, the therapeutic efficacy of PDT is often compromised by tumor hypoxia. Due to the abnormal vasculature of the TME, oxygen delivery is insufficient, resulting in limited ROS production and reduced treatment outcomes.193,194 To overcome this limitation, the combined application of PTT and PDT has been explored. PTT-induced hyperthermia can dilate tumor blood vessels, accelerate local blood flow, and improve oxygen supply. Simultaneously, elevated temperature can inhibit the mitochondrial respiratory chain of tumor cells, reduce oxygen consumption, decrease hemoglobin oxygen affinity, and promote oxygen release into tumor tissues.195–197

Nanomaterials play a crucial role in ameliorating tumor microenvironment hypoxia during PTT and PDT treatments. For example, Fe3O4@MnO nanospheres can be magnetically targeted to tumor sites, where they catalyze the decomposition of H2O2 in the TME to generate oxygen.198 Similarly, oxygen nanocarriers such as PFC@Fe3O4 nanoparticles can directly deliver oxygen to tumors, thereby improving local oxygenation.199 Some nanomaterial complexes can simultaneously exert PTT and PDT functions; for instance, CP-TPP/Au/PEG nanospheres enable dual activation: the PTT effect under 808 nm irradiation and the PDT effect under 630 nm irradiation.200 In addition, nanomaterials can enhance therapeutic efficacy through synergistic effects, facilitate the targeted delivery of photosensitizers and photothermal agents, and generally exhibit good biocompatibility with low toxicity195,201,202 In the study by Tan et al, when PLGA nanoparticles loaded with the photosensitizer indocyanine green (ICG) were applied in the treatment of tongue squamous cell carcinoma. Upon NIR irradiation, ICG generated localized hyperthermia to kill tumor cells while simultaneously producing ROS