Sustainable biogenic synthesis of silver nanoparticles for oral cancer: a comprehensive review

The increasing incidence of oral malignancies, coupled with the limitations of conventional treatments such as toxicity and drug resistance, has driven the exploration of novel therapeutic approaches. Silver nanoparticles (AgNPs) have emerged as promising anticancer agents due to their distinctive physicochemical attributes, which facilitate antimicrobial, anti-inflammatory, and tumor-suppressive activities. Unlike traditional chemical or physical synthesis methods, plant-mediated green synthesis offers a sustainable and ecologically sound alternative, leveraging the natural reducing and stabilizing compounds inherent in botanical extracts. This review provides a detailed analysis of contemporary advancements in the eco-conscious production of AgNPs using diverse plant sources and their potential role in addressing oral cancer. Furthermore, the article evaluates the cytotoxic impact of these biogenic nanoparticles on oral cancer cell models, elucidating molecular pathways such as oxidative stress induction, apoptosis activation, and inhibition of proliferative signaling. Clinical implications are explored, emphasizing the balance between therapeutic efficacy and biocompatibility in normal cells. While plant-derived AgNPs present a groundbreaking avenue for targeted oral cancer therapy, challenges such as scalability, standardization, and long-term safety require resolution for successful clinical translation. This synthesis of current knowledge aims to inspire innovative, nature-driven strategies to enhance oral oncology outcomes.

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT |

1 Introduction

Oral carcinoma represents a significant global public health challenge, ranking as one of the most prevalent malignancies globally (Sekar K. et al., 2025). This heterogeneous group of cancers affects multiple anatomical sites within the oral cavity, including the lips, tongue, buccal mucosa, gingivae, floor of the mouth, palatal regions, sinuses, and pharynx (Prasad et al., 2025). Established etiological factors driving its development include tobacco consumption (smoked or chewed), chronic alcohol use, persistent human papillomavirus (HPV) infection, and prolonged ultraviolet (UV) radiation exposure, all of which synergistically contribute to its elevated incidence and mortality rates (Figure 1) (Sivalingam, 2025). A critical barrier to improving patient outcomes is the frequent absence of discernible symptoms during early disease progression, leading to delayed diagnosis and unfavourable prognoses. Late clinical presentation is commonly associated with locally advanced or metastatic tumors, complicating therapeutic interventions (Paluchamy and Stephen, 2025).

Figure 1

Figure 1. Plant extract-mediated green synthesis of AgNPs. The schematic illustrates how phytochemicals such as polyphenols, flavonoids, terpenoids, and proteins act as reducing agents to convert Ag⁺ into metallic Ag⁰ and simultaneously serve as stabilizing/capping agents to prevent aggregation.

Although medical technology has progressed considerably, traditional therapeutic approaches for oral cancer still face notable limitations (Mahalakshmi et al., 2025; Veeraraghavan et al., 2025). Surgical interventions, while necessary for tumor removal, can lead to disfigurement and functional impairments, affecting both appearance and quality of life (Krishnan et al., 2025a; Sekar R. et al., 2025). Radiation therapy, though effective in targeting localized tumors, can cause severe side effects, including mucositis, dermatitis, and long-term damage to surrounding healthy tissues (Prabhuvenkatesh et al., 2025; Sowmya et al., 2025). Chemotherapy continues to serve as a cornerstone in cancer treatment. However, its lack of specificity frequently results in extensive systemic toxicity. Adverse effects such as severe nausea, emesis, alopecia, and bone marrow suppression are prevalent, compromising immune defenses and elevating risks of opportunistic infections (Abhinav et al., 2024; Hussain et al., 2025; Saklecha et al., 2025). Beyond acute toxicities, the persistent challenges of intrinsic or acquired chemoresistance and frequent disease relapse significantly undermine therapeutic success (Gondivkar et al., 2024; Patel et al., 2025). Neoplastic cells may evolve adaptive pathways to circumvent drug-induced cytotoxicity, including enhanced drug efflux, DNA repair activation, and apoptotic signaling dysregulation (Patel and Kumar, 2025; Venkatesh et al., 2025). These resistance mechanisms contribute to diminished treatment responsiveness, necessitating the development of precision-based therapies to overcome such barriers (Krishnan et al., 2025b). Addressing these limitations is critical to improving survival rates and reducing the burden of treatment-related morbidity in cancer care (Sarathy et al., 2025). The shortcomings of conventional therapies highlight the urgent need for novel strategies capable of addressing these challenges and enhancing patient prognosis (Sah et al., 2025).

Nanotechnology has emerged as a transformative tool in cancer therapy, offering novel solutions for improved diagnosis, targeted drug delivery, and enhanced therapeutic efficacy (Herin et al., 2024; Kaliyaperumal et al., 2025a; Kannan and Sivaperumal, 2025; Lakshmikanth et al., 2025). Nanoparticles, due to their unique physicochemical properties, can be engineered to interact specifically with cancer cells, thereby reducing the impact on healthy tissues and minimizing side effects (Rahiman et al., 2024; Gajendiran et al., 2025; Thirunavukkarasu et al., 2025; Tripathi et al., 2025). The ability of nanoparticles to cross biological barriers and deliver therapeutic agents directly to the target site enhances drug bioavailability and efficacy (Kamarulazam et al., 2025; Thomas et al., 2025). Advances in nanotechnology have revolutionized cancer therapeutics through the development of diverse nanoscale platforms, such as liposomes, dendrimers, and metallic nanoparticles (Jansirani et al. 2025; Kaliyaperumal et al., 2025b; Kaliyaperumal et al., 2025c). Liposomes, lipid-based nanocarriers, excel in encapsulating therapeutic agents, shielding them from enzymatic degradation while enabling spatial and temporal control over drug release (Balaraman et al., 2024; Govindasamy et al., 2025; Shaikh et al., 2025). Dendrimers, characterized by their hyperbranched architecture, offer versatile surface functionalization with ligands, antibodies, or imaging probes, enhancing tumor-specific targeting and multi-agent delivery (Elumalai and Srinivasan, 2025; Kaliyaperumal et al., 2025d). Metallic nanoparticles, including gold and silver variants, leverage plasmonic resonance and photothermal capabilities for applications such as image-guided therapy and localized hyperthermia (Ryntathiang et al.; Imath et al., 2025; Vasudevan et al., 2025). These innovations not only enhance therapeutic accuracy by concentrating drug action at tumor sites but also enable the creation of biocompatible, multimodal treatment regimens that minimize off-target toxicity (Phouheuanghong et al., 2025; Shabnum et al., 2025; Vijay et al., 2025). By integrating diagnostics and therapeutics, nanotechnology bridges critical gaps in conventional oncology, offering scalable solutions to improve treatment efficacy and patient safety (Ravi et al., 2024).

AgNPs have garnered significant attention in oral oncology due to their unique combination of physicochemical and biological properties that distinguish them from other metallic nanoparticles. Their nanoscale size and high surface-to-volume ratio enable enhanced cellular uptake and intimate interactions with cancer cells, resulting in more efficient therapeutic effects (J et al., 2025; Madhukriti et al., 2025). Unlike many other metal-based nanoparticles, AgNPs exhibit a broad spectrum of bioactivities, including potent antimicrobial, anti-inflammatory, and selective anticancer effects, which are particularly valuable in the complex oral microenvironment often complicated by infections and inflammation. This multifunctionality allows AgNPs not only to directly target and kill malignant cells but also to mitigate infection-related complications that can compromise treatment outcomes. Mechanistically, AgNPs induce cancer cell death via reactive oxygen species (ROS) generation, mitochondrial disruption, DNA damage, and interference with critical cell survival pathways such as PI3K/Akt, which collectively promote apoptosis and inhibit tumor proliferation (Palanisamy et al., 2025; Pandiyarajan et al., 2025). Compared to other metallic nanoparticles like gold or copper, silver offers a cost-effective and scalable option, with proven clinical safety profiles and fewer concerns related to chronic toxicity or accumulation (Swathi et al., 2025). Additionally, silver’s unique capacity to disrupt microbial biofilms complements oral cancer therapy by reducing secondary infections and inflammation, addressing a key challenge in oral oncology. The ease of green synthesis and surface functionalization further enhances the versatility of AgNPs, enabling tailored therapeutic designs that improve targeting and minimize off-target effects. Taken together, these biomedical advantages make AgNPs an exceptionally promising and reader-friendly choice for advancing precision therapy in oral cancer, combining therapeutic efficacy with safety and multifunctional benefits that other metallic nanoparticles may not fully provide (Wilson et al., 2025).

The plant-mediated green synthesis of AgNPs offers distinct environmental and clinical advantages compared to conventional chemical or physical methods (Asha et al., 2024; Velmurugan et al., 2024; Kirubakaran et al., 2025). By leveraging phytochemical-rich extracts—abundant in polyphenols, flavonoids, and terpenoids—this approach replaces synthetic reductants and stabilizers, eliminating hazardous reagents and energy-intensive processes (Ashokkumar et al., 2024; Govindharaj et al., 2024; Natrayan et al., 2025). These bioactive phytoconstituents not only reduce silver ions to nanoparticles but also coat their surfaces, enhancing colloidal stability and biocompatibility. The resulting biogenic AgNPs exhibit reduced cytotoxicity toward healthy cells, a critical factor for minimizing off-target effects in therapeutic applications (Bhuvaneshwari et al., 2024; Wong et al., 2024; Subramanian et al., 2025). Moreover, this method aligns with sustainable practices by reducing waste generation and energy consumption, while its scalability and cost-efficiency support industrial translation. The inherent biocompatibility of plant-derived capping agents further enhances the nanoparticles’ biosafety profile, enabling their integration into clinical regimens for oral cancer (Bhuvaneshwari et al., 2024). Collectively, green synthesis represents an ecologically responsible and clinically viable strategy, bridging nanotechnology and natural product chemistry to advance oncological care (Yasodha et al., 2024). Oral cancer poses significant health challenges due to difficulties in early diagnosis and the limitations of traditional treatments. AgNPs, through nanotechnology, present a promising alternative by offering targeted therapy and reduced side effects (Archana and Menon, 2024). The eco-friendly green synthesis of AgNPs using plant extracts enhances their biocompatibility for oral cancer treatment (Hemavathy et al., 2024). This review focuses on recent developments in biogenic AgNPs for treating oral cancer, examining their synthesis, characterization, and therapeutic mechanisms. It also contrasts AgNPs with conventional therapies, addresses production and clinical integration issues, and emphasizes the advantages of using plant extracts in their synthesis.

2 Green synthesis of silver nanoparticles

2.1 Comparison with traditional synthesis methods

Green synthesis of AgNPs offers several advantages over traditional physical and chemical methods. Conventional methods often involve high energy inputs, hazardous chemicals, and complex procedures (Subhalakshmi et al., 2024). For example, chemical reduction methods use toxic reducing agents like sodium borohydride, while physical methods such as laser ablation require sophisticated equipment and high energy (Sivalingam and Pandian, 2024). In contrast to conventional synthesis techniques, plant-mediated green synthesis offers an ecologically sustainable, economically viable, and operationally simple approach. By replacing synthetic reagents with phytochemicals, this method circumvents the use of hazardous chemicals and minimizes ecological footprints (Sivalingam et al., 2024c). Furthermore, biogenic AgNPs exhibit superior biocompatibility, as natural capping agents derived from plant extracts reduce cytotoxicity and enhance biosafety in biological systems (Baskaran et al., 2024). Despite these benefits, traditional synthesis routes often achieve finer control over nanoparticle morphology (e.g., size uniformity, geometric precision), prompting ongoing efforts to refine green synthesis protocols for enhanced reproducibility and structural predictability (Pushpanathan et al., 2025).

Plant-based green synthesis represents a transformative paradigm for producing AgNPs with applications in oncology, particularly oral cancer treatment. By elucidating the interplay between phytochemical composition, reaction kinetics, and nanoparticle properties, researchers can engineer AgNPs with customizable physicochemical profiles (Arumugam et al., 2024). Advances in process optimization—such as modulating reaction pH, temperature, and precursor ratios—will enable the scalable production of nanoparticles tailored for targeted drug delivery, photothermal therapy, or diagnostic imaging (Sudhashini et al., 2025). This sustainable methodology not only aligns with global eco-conscious initiatives but also bridges the gap between nanomedicine innovation and clinical translation, offering a roadmap for next-generation cancer therapeutics (Anandapillai et al., 2024).

2.2 Commonly used medicinal plants for biogenic silver nanoparticle synthesis

Optimal plant species for AgNP synthesis are chosen based on their phytochemical richness, geographic availability, and compatibility with biomedical goals (Table 1) (Habeeb Rahuman et al., 2022). Species like Azadirachta indica (neem), Camellia sinensis (green tea), and Ocimum sanctum (tulsi) are prioritized for their high concentrations of antioxidants (e.g., catechins, terpenoids), which accelerate silver ion reduction while imparting therapeutic properties to the nanoparticles (Pugazhendhi et al., 2018; Zhang et al., 2019; Gokulakrishnan et al., 2024; Karunakar et al., 2024; Pauline et al., 2025). Biocompatibility assessments further guide selection, ensuring minimal cytotoxicity toward healthy tissues and alignment with drug delivery requirements. This strategic selection enhances nanoparticle functionality for applications such as targeted cancer therapy (David et al., 2021; Agarwal et al., 2025).

Table 1

Table 1. Commonly used medicinal plants for biogenic silver nanoparticle synthesis.

2.3 Optimization of synthesis conditions

Optimization of synthesis conditions requires quantitative control of precursor concentration, extract ratios, pH, temperature, and reaction duration (Table 2) (Sivalingam et al., 2024b). For example, most reproducible studies utilize AgNO₃ concentrations between 0.five to five mM, extract-to-metal salt ratios ranging from 1:5 to 1:20, and alkaline pH (9–11), which enhances polyphenol-mediated reduction (Habib et al., 2024). Temperature ranges of 40 °C–80 °C significantly accelerate reaction kinetics and improve nucleation uniformity. These quantitative boundaries are essential for achieving consistent AgNP morphology and have been incorporated into this revised review to enhance methodological rigor and reproducibility (Balamurugan et al., 2024; Bekele et al., 2024; Hemavathy et al., 2024; Nandhini et al., 2024; Sangameshwaran et al., 2024).

Table 2

Table 2. Standardized parameter ranges for reproducible plant-mediated AgNP synthesis.

2.3.1 Quantitative parameters governing reproducible green synthesis of AgNPs

Achieving reproducibility in plant-mediated green synthesis of AgNPs requires precise control over quantitative reaction parameters rather than relying solely on descriptive or qualitative accounts. Variability in extract composition, precursor strength, reaction temperature, and pH often results in substantial differences in nanoparticle size, morphology, and stability. To overcome these inconsistencies, it is essential to establish well-defined operational windows for each major synthesis variable. Across the literature, including the studies reviewed in this manuscript, optimized conditions generally fall within specific ranges that influence the nucleation and growth phases of AgNP formation. Clearly articulating these ranges provides a standardized reference that enhances the reproducibility of green-synthesis protocols (Fahim et al., 2024).

One of the most influential parameters in AgNP synthesis is the concentration of silver nitrate (AgNO₃), the metal precursor. Most studies report successful nanoparticle formation within the 0.5–5 mM concentration range. Concentrations above 5 mM often lead to excessive nucleation bursts, resulting in larger and highly polydisperse particles, while levels below 0.5 mM slow reduction kinetics and may lead to incomplete conversion of Ag⁺ to Ag⁰. Therefore, maintaining precursor concentration within this window is critical for balancing reaction speed and particle uniformity (Kaabipour and Hemmati, 2021).

Equally important is the ratio of plant extract to metal precursor, typically maintained between 1:5 and 1:20 (v/v). Extract-rich systems produce rapid nucleation due to higher availability of reducing phytochemicals, which generally yields smaller, more uniform nanoparticles. Conversely, higher volumes of AgNO₃ relative to extract favour slower nucleation and often result in larger crystalline structures. Because the phytochemical load varies significantly between plant species, the optimal extract-to-precursor ratio must be guided by the concentration of active metabolites such as polyphenols and flavonoids (Keskin et al., 2025).

The pH of the reaction mixture also plays a decisive role in the kinetics and quality of AgNP synthesis. Effective synthesis most commonly occurs within a pH range of 7–11. Under alkaline conditions (pH 9–11), ionization of polyphenolic groups enhances their electron-donating capacity, enabling faster Ag⁺ reduction and promoting the formation of stable, monodisperse spherical nanoparticles. In contrast, acidic conditions (pH <6) suppress reduction rates and weaken the capping efficiency of phytochemicals, often leading to aggregation and inconsistent nanoparticle morphology. Thus, controlling pH is essential for obtaining predictable and reproducible outcomes (Miranda et al., 2022).

Temperature conditions further influence nanoparticle formation through their effect on reaction kinetics. The optimal synthesis temperature generally lies between 40 °C and 80 °C. Increasing the temperature above 60 °C accelerates reaction rates in accordance with Arrhenius kinetics, promoting rapid nucleation, although excessive heating may also trigger uncontrolled growth and polydispersity. While room-temperature synthesis (25 °C–30 °C) is feasible, it typically proceeds more slowly and may not yield highly uniform nanoparticles without prolonged incubation (Ansari et al., 2023).

Reaction time, which is inherently linked to all the preceding parameters, typically ranges from 20 to 90 min for complete reduction of Ag⁺. The duration required depends on extract potency, precursor concentration, and temperature. Monitoring the reaction through UV–Vis spectroscopy, specifically by tracking the surface plasmon resonance (SPR) band between 400 and 450 nm, helps confirm the progression and completion of nanoparticle synthesis (Di Fraia et al., 2025).

From a mechanistic standpoint, the interplay between nucleation and growth processes largely determines the final nanoparticle characteristics. Fast nucleation followed by slow growth produces smaller and more stable spherical nanoparticles, whereas slow nucleation accompanied by rapid autocatalytic growth results in larger or anisotropic structures. The phytochemical composition of the plant extract—particularly the presence of strong electron-donating molecules—plays a central role in shaping these kinetic profiles. By defining and optimizing these quantitative parameters, researchers can significantly improve the reproducibility and predictability of biogenic silver nanoparticle synthesis (Jiang et al., 2010).

2.4 Mechanisms of plant extract mediated synthesis

The plant-mediated green synthesis of AgNPs leverages the redox activity of phytochemicals to convert ionic silver (Ag⁺) into metallic nanoparticles (Ag⁺ → Ag⁰). This process initiates with the preparation of aqueous or solvent-based plant extracts, where heating plant materials (e.g., leaves, roots, or flowers) releases bioactive constituents such as polyphenols, flavonoids, and proteins (Figure 1) (Brindhadevi et al., 2021; Kaliaperumal et al., 2023; Muruganandham et al., 2023). These biomolecules act as dual-function agents: reducing silver ions to nucleate nanoparticles and coating their surfaces to regulate growth and prevent aggregation (Subramaniam et al., 2021; Kingslin et al., 2023). The phytochemical diversity across plant species leads to variations in nanoparticle morphology (e.g., spherical, triangular) and colloidal stability, underscoring the role of specific metabolites in directing synthesis kinetics (Dilipan et al., 2023; Lavanya et al., 2023; Vijayaraj et al., 2023).

3 Characterization of green synthesized silver nanoparticles

Characterizing biogenic AgNPs requires careful consideration of methodological artifacts and the unique influence of phytochemical capping agents, as these factors can significantly distort measurements if not properly accounted for. Unlike chemically synthesized nanoparticles, biogenic AgNPs are enveloped by complex organic coronas composed of polyphenols, flavonoids, proteins, terpenoids, and polysaccharides from plant extracts. These biomolecular layers alter hydrodynamic size, surface charge, optical properties, and stability profiles, making it essential to interpret characterization data within the context of their biological origin (Ezhumalai et al., 2025).

UV–Vis spectroscopy remains the first-line analytical tool for monitoring the formation and stability of AgNPs through surface plasmon resonance (SPR) absorption. However, in green-synthesized systems, SPR peak position and bandwidth are strongly influenced by extract composition. Polyphenol-rich extracts typically produce sharp SPR bands (∼410–430 nm), while protein- or carbohydrate-dense extracts can broaden the peak due to thicker capping layers and altered electron density around the metallic core. Spectral redshifts over time often indicate Ostwald ripening or phytochemical oxidation, whereas blueshifts can reflect capping-induced stabilization. Thus, SPR interpretation must integrate the chemical signatures of the capping matrix rather than attributing shifts solely to size variation (Michael et al., 2024).

Transmission Electron Microscopy (TEM) remains the gold standard for observing nanoparticle morphology, but it is not without limitations. Biogenic AgNPs can undergo structural changes during drying on TEM grids, including shrinkage of the organic corona, formation of artificial aggregates, or flattening of the metallic core. These artifacts can lead to underestimation of true particle diameter or the false appearance of polydispersity. High-resolution TEM can partially mitigate these issues by enabling lattice imaging; however, complementary techniques such as cryo-TEM provide more accurate insights by preserving the native hydrated state of biogenic nanoparticles (Suriyakala et al., 2024).

Scanning Electron Microscopy (SEM) complements TEM by mapping surface topography and textural features of AgNPs. Coupled with Energy Dispersive X-ray Spectroscopy (EDX), SEM enables elemental composition profiling, verifying silver content and detecting trace elements (e.g., oxygen, carbon) from phytochemical coatings. This combination validates successful bioreduction and identifies impurities in synthesized nanoparticles (Ganesan T. et al., 2024).

Dynamic Light Scattering (DLS) provides valuable information on hydrodynamic diameter, but the technique is highly sensitive to the outer hydration shell and the thickness of the organic corona. In green-synthesized AgNPs, the hydrodynamic diameter reported by DLS is almost always larger than TEM-derived core size due to the presence of phytochemical capping agents. Furthermore, DLS disproportionately weights larger aggregates, meaning that even a small degree of agglomeration can inflate the average size. Therefore, DLS values must be interpreted as “effective hydrodynamic dimensions” rather than true metallic core sizes (Gheisari et al., 2024).

X-ray Diffraction (XRD) deciphers the crystalline architecture of AgNPs by generating Bragg diffraction patterns. Distinct peaks corresponding to face-centered cubic (FCC) silver lattice planes (e.g., 111, 200) confirm metallic silver formation, while crystallite size calculations via Scherrer’s equation correlate with nanoparticle dimensions observed in microscopy (Prabakaran et al., 2024).

Fourier Transform Infrared Spectroscopy (FTIR) is crucial for identifying functional groups responsible for reduction and stabilization. However, extract-derived macromolecules introduce overlapping vibrational bands (e.g., O–H, C=O, C–N) that can obscure weaker Ag–ligand interactions. Interpretation therefore requires careful comparison with spectra of pure extracts to differentiate between phytochemical signatures and nanoparticle-associated shifts. For example, attenuation or slight shifts in carbonyl or hydroxyl peaks can suggest ligand binding to the AgNP surface (Sivalingam et al., 2024a).

Zeta potential analysis provides insights into colloidal stability; however, in green-synthesized systems the measured values often reflect contributions from ionized phytochemicals rather than intrinsic metallic surface charge. Extract-derived anionic groups such as carboxylates and phenolates typically impart strong negative zeta potentials (−20 to −35 mV), which enhance stability but complicate direct comparison with chemically capped nanoparticles. Long-term stability measurements must therefore account for the slow oxidation or desorption of capping agents, which leads to gradual zeta potential reduction (Liaqat et al., 2022).

Together, these refined characterization strategies highlight that analyzing green-synthesized AgNPs requires more than routine spectral or microscopic assessment. Understanding the interplay between measurement artifacts and phytochemical capping is essential for accurately determining nanoparticle morphology, optical behavior, and long-term stability, reinforcing the importance of critical interpretation in green nanotechnology research (Nongthombam et al., 2024).

The properties of biogenically synthesized AgNPs are intrinsically shaped by the phytochemical composition and concentration of plant extracts employed during fabrication. These extracts serve as reservoirs of bioactive constituents—including flavonoids, alkaloids, tannins, and polyphenols—that orchestrate reduction, capping, and stabilization processes. Such compounds govern critical AgNP features such as size, geometry, surface functionality, and colloidal stability, which collectively dictate their biological efficacy and suitability for therapeutic or industrial applications (Al Baloushi et al., 2024; Gokulakrishnan et al., 2024).

Size and Shape: The size and geometry of AgNPs are modulated by the redox potential and concentration of phytochemicals in plant extracts. Polyphenol-rich extracts, for example, accelerate silver ion reduction, promoting rapid nucleation and yielding smaller, monodisperse nanoparticles (Khan et al., 2023). In contrast, extracts with milder reductants favor slower nucleation kinetics, often producing larger or irregularly shaped particles. This kinetic control enables the design of spherical, rod-like, or polyhedral nanostructures, with morphology directly influencing applications such as photothermal therapy or drug encapsulation. Tailored synthesis protocols using species like Azadirachta indica or Camellia sinensis demonstrate how phytochemical diversity can be harnessed to achieve precision in nanoparticle architecture (Aiswarriya et al., 2023; Rajalakshmi et al., 2023; Sridharan et al., 2023; Sudhisha et al., 2023).

Surface Chemistry: Beyond reduction, phytochemicals adsorb onto AgNP surfaces, forming organic coronas that prevent aggregation and confer stability. Functional groups such as hydroxyl (–OH), carboxyl (–COOH), and amine (–NH₂) residues within these capping layers mediate interactions with biological targets. For instance, carboxyl-rich surfaces enhance nanoparticle affinity for cellular membranes, while phenolic coatings may amplify antioxidant or antimicrobial effects. Such surface engineering, dictated by plant extract composition, enables customization of AgNP behavior in physiological environments, optimizing them for roles like targeted drug delivery or biofilm disruption (Pugazhendhi and Jayavel, 2023).

Biocompatibility: A hallmark of plant-synthesized AgNPs is their reduced cytotoxicity compared to chemically produced counterparts. Phytochemical-derived capping agents, such as terpenoids or proteins, create biocompatible interfaces that minimize unintended interactions with healthy cells. This intrinsic biosafety is critical for in vivo applications, where uncontrolled nanoparticle aggregation or oxidative stress could provoke adverse immune responses. Studies using Aloe vera-capped AgNPs, for example, demonstrate enhanced tolerability in mammalian cells, underscoring the role of plant-specific metabolites in balancing therapeutic potency with biocompatibility (Bohra et al., 2021; Agarwal et al., 2025).

The selection of plant extracts thus serves as a tunable lever for dictating AgNP properties. By correlating phytochemical profiles with nanoparticle characteristics—such as using high-flavonoid extracts for small, stable particles or terpenoid-rich species for enhanced biocompatibility—researchers can tailor AgNPs for specific biomedical, environmental, or industrial uses. This phytochemical-driven approach not only aligns with green chemistry principles but also expands the functional versatility of AgNPs, positioning them as next-generation tools in precision medicine and sustainable technology (Barabadi et al., 2021).

The stability and morphology of synthesized AgNPs are of paramount importance for their effective use, particularly in biomedical applications. These properties dictate how AgNPs behave in biological environments and influence their therapeutic potential, making them critical factors in the design and application of nanomaterials (Acharya et al., 2022).

Stability, in the context of AgNPs, refers to the ability of the nanoparticles to remain evenly dispersed in a solution without undergoing aggregation over time. This is a vital consideration because aggregation can lead to the formation of larger particles, which may alter the nanoparticles’ physical and chemical properties, reducing their effectiveness and potentially increasing their toxicity (Barabadi et al., 2022). The stability of AgNPs is largely determined by the nature of the capping agents provided by plant extracts during the synthesis process. These capping agents, often phytochemicals such as polyphenols, proteins, and flavonoids, coat the surface of the nanoparticles, providing a barrier that prevents them from coming into close contact and aggregating. This barrier can work through electrostatic or steric hindrance, depending on the nature of the capping agent, thereby maintaining the nanoparticles’ stability in the solution (Ramasamy et al., 2024). The stability of AgNPs can be assessed by monitoring changes in their UV-Vis spectra over time, where a shift in the absorbance peak may indicate aggregation. Zeta potential measurements are also crucial for evaluating the surface charge of the nanoparticles, with higher absolute zeta potential values indicating greater stability due to increased repulsion between particles (Krishnamoorthy et al., 2023).

Morphology, including the shape and size of AgNPs, is another critical factor that influences their behavior and effectiveness in biomedical applications. The shape of AgNPs, whether spherical, rod-shaped, triangular, or otherwise, can affect how these particles interact with biological systems, including their cellular uptake, biodistribution, and overall biocompatibility. Spherical nanoparticles are often preferred in biomedical applications due to their uniform shape, which facilitates predictable interactions with cells and other biological molecules. Detailed morphological analysis of AgNPs is typically conducted using TEM and SEM, which provide high-resolution images of the nanoparticles, allowing for precise determination of their shape and size distribution (Rama et al., 2023).

Aggregation of AgNPs is a significant concern as it can severely compromise their efficacy and safety, particularly in therapeutic applications. Aggregated nanoparticles may exhibit altered surface chemistry, reduced surface area, and diminished biological activity. The presence of phytochemicals that strongly bind to the surface of AgNPs plays a crucial role in maintaining monodispersity, preventing aggregation. Techniques such as DLS and zeta potential measurements are commonly employed to assess the degree of aggregation, providing valuable insights into the stability of the nanoparticles in various conditions (Sivalingam and Pandian, 2025; Sivalingam et al., 2024a).

The thorough characterization of biogenic AgNPs synthesized using plant extracts is crucial for understanding their properties and optimizing their application in oral cancer therapy. The influence of plant extracts on nanoparticle properties underscores the importance of selecting appropriate plant species and optimizing synthesis conditions to produce AgNPs with desirable characteristics.

4 In vitro applications of biogenic silver nanoparticles for oral cancer

4.1 In Vitro studies on oral cancer cell lines

In vitro analyses are pivotal for assessing the antineoplastic potential of plant-derived AgNPs against oral carcinoma (Table 3) (Budi and Farhood, 2023). These investigations focus on cellular responses—such as viability, apoptotic induction, ROS generation, and cell cycle arrest—in oral cancer lines (e.g., SCC-4, SCC-9, CAL 27, KB) following exposure to varying AgNP concentrations. Such studies elucidate mechanisms of action and therapeutic windows, guiding translational development (Subramanyam et al., 2021; Shukla and Senapathya, 2025).

Table 3

Table 3. Plant-mediated silver nanoparticles (AgNPs) with reported cytotoxicity against cancer cell lines.

Subramanyam et al. (2023) reported the green synthesis of AgNPs using Byttneria herbacea leaf extract (BH-AgNPs), emphasizing their application in oral oncology. UV-Vis spectroscopy revealed a time-dependent surface plasmon resonance (SPR) redshift from 422 nm to 437 nm, confirming nanoparticle maturation. TEM and DLS analyses identified spherical BH-AgNPs with an average diameter of 8 nm and high colloidal stability (zeta potential: 21 mV). The nanoparticles exhibited robust antioxidant activity, neutralizing free radicals, and potent antibacterial effects against Escherichia coli and Staphylococcus aureus. In KB oral cancer cells, BH-AgNPs demonstrated significant cytotoxicity (IC₅₀: 89.25 μL/mL), inducing apoptosis via ROS-mediated pathways. These findings position BH-AgNPs as a dual-functional platform for oral cancer therapy, merging anticancer efficacy with antimicrobial protection (Subramanyam et al., 2023).

Barua et al. (2017) synthesized AgNPs using Thuja occidentalis leaf extract, highlighting their biocompatibility and anticancer versatility. The spherical nanoparticles (12.7 nm average size) exerted concentration-dependent cytotoxicity (6.25–50 μg/mL) against breast (MCF-7, MDA-MB-231), cervical (HeLa), and oral (KB) cancer lines, while sparing normal human PBMCs and rat hepatocytes. This selectivity underscores their biosafety profile. Additionally, the AgNPs displayed broad-spectrum antibacterial activity against pathogens like Staphylococcus aureus and Pseudomonas aeruginosa. The study underscores the potential of phytogenic AgNPs as multitarget agents, capable of synergizing anticancer and antimicrobial actions with minimal off-target toxicity (Barua et al., 2017). Both studies underscore the therapeutic potential of plant-synthesized AgNPs in oral cancer, highlighting key advantages including eco-sustainable synthesis via plant extracts that reduce reliance on toxic reagents, multifunctionality through dual anticancer and antimicrobial actions to address comorbidities like infections, and enhanced biocompatibility due to natural capping agents that minimize off-target cytotoxicity, thereby improving therapeutic indices. These preclinical findings emphasize the need for further in vivo validation and clinical trials to translate phytogenic AgNPs into next-generation, precision-based therapies for oral oncology, bridging green chemistry innovations with unmet clinical needs.

Fundamental evaluations of biogenic AgNPs in oral cancer research prioritize cell viability assays, such as MTT, MTS, and Alamar Blue, which quantify metabolic activity through enzymatic reduction of tetrazolium salts into formazan. These assays reveal concentration-dependent reductions in viability, reflecting AgNP-induced cytotoxicity, where higher nanoparticle concentrations correlate with diminished cancer cell survival (Karthikeyan et al., 2024; Rathi and Ramesh, 2024; Vanti et al., 2024).

Recent studies highlight the therapeutic versatility of plant-synthesized AgNPs. Alsareii et al. (2022) utilized Rhizophora apiculata leaf extract to produce AgNPs (35–100 nm) via eco-friendly methods, demonstrating potent antioxidant, anti-inflammatory, and cytotoxic effects against oral, lung, and skin cancer lines. Enhanced wound closure and cell migration further underscored their biomedical potential (Alsareii et al., 2022). Similarly, Huang Fang (2022) synthesized AgNPs (26.11 nm average size) from Rheum ribes L. leaves, observing significant dose-dependent cytotoxicity in oral cancer cells (HSC-2, HSC-3, HSC-4) at IC₅₀ values of 125–250 μg/mL, linked to their antioxidant activity (Fang, 2022). Yan et al. (2022) reported spherical AgNPs (50–90 nm) from Salvia officinalis, which selectively targeted oral squamous carcinoma cells (KB, HSC-2, HSC-3, Ca9-22) while sparing normal HUVEC cells, with cytotoxicity attributed to ROS modulation and antioxidant mechanisms (Yan et al., 2022). Collectively, these studies validate the role of green synthesis in producing biocompatible, multifunctional AgNPs. Characterization via SEM, XRD, and FTIR confirmed structural integrity and phytochemical capping, while dose-responsive cytotoxicity and selective action against malignant cells highlight their therapeutic promise. The integration of antioxidant properties with anticancer efficacy positions plant-derived AgNPs as innovative candidates for oral oncology, warranting clinical exploration to translate preclinical findings into targeted therapies.

Beyond assessing cell viability, researchers analyze morphological transformations in cancer cells to evaluate nanoparticle-mediated toxicity. Microscopy-based assessments reveal structural anomalies such as cytoplasmic condensation, membrane protrusions (blebbing), and chromatin fragmentation—hallmark indicators of apoptotic pathways—or cellular swelling and membrane rupture suggestive of necrotic processes. These visual biomarkers corroborate the cytotoxic impact of AgNPs, offering spatial insights into cell death mechanisms (Oviya et al., 2023; Paramasivam et al., 2023).

To differentiate apoptotic from necrotic outcomes, advanced assays are employed. Flow cytometry using Annexin V/propidium iodide dual staining quantifies phosphatidylserine externalization (apoptosis) versus membrane permeability (necrosis). Complementary techniques like TUNEL assays detect DNA strand breaks, while caspase activation profiling (e.g., caspase-3/7 activity) maps enzymatic pathways driving programmed cell death. These methods collectively validate apoptosis as a primary mode of AgNP-induced cytotoxicity (Sabirova et al., 2025).

ROS generation is a critical mediator of AgNP toxicity. Elevated intracellular ROS flux, measured via fluorogenic probes (e.g., DCFH-DA), disrupts redox equilibrium, inducing oxidative damage to lipids, proteins, and DNA. This oxidative stress activates stress-responsive kinases (e.g., JNK, p38 MAPK) and mitochondrial permeability transition, culminating in caspase-dependent apoptosis (Ashique et al., 2022; Harsha et al., 2022; Loganathan et al., 2022).

Cell cycle modulation further elucidates AgNP anticancer mechanisms. Flow cytometric DNA content analysis identifies phase-specific arrests (e.g., G0/G1, S, or G2/M), linking nanoparticle exposure to proliferative inhibition. Such arrests often correlate with cyclin-dependent kinase suppression or checkpoint kinase activation, providing mechanistic targets for therapeutic optimization (Garapati et al., 2022).

Dziedzic et al. investigated nanoscale AgNPs (10 nm) against SCC-25 tongue carcinoma, revealing dose- and time-dependent antiproliferative effects (IC₅₀: 5.19 μg/mL at 48 h). AgNPs induced G0/G1 phase arrest and upregulated pro-apoptotic Bax/Bcl-2 ratios, triggering mitochondrial apoptosis. Intriguingly, co-treatment with berberine—an isoquinoline alkaloid—attenuated AgNP cytotoxicity at higher doses, suggesting antagonistic interactions potentially mediated by nanoparticle-alkaloid complexation. This finding underscores the need to evaluate combinatorial regimens, as phytochemical adjuvants may inadvertently diminish AgNP efficacy (Dziedzic et al., 2016). These methodologies—morphological analysis, apoptosis profiling, ROS quantification, and cell cycle tracking—collectively decode AgNP bioactivity. While AgNPs alone exhibit potent, ROS-driven anticancer effects, their interplay with co-administered compounds like berberine necessitates careful evaluation to optimize therapeutic outcomes in oral oncology.

4.2 Mechanisms of anticancer activity of biogenic AgNPs in oral malignancies

The anticancer effects of green-synthesized silver nanoparticles (AgNPs) against oral cancer cells are controlled not by general mechanisms like ROS generation or mitochondrial depolarization alone, but by highly specific physicochemical properties of the nanoparticles themselves. Key factors such as particle size, shape, surface charge, ligand chemistry, dissolution kinetics, and the phytochemical corona collectively determine how AgNPs interact with cancer cell membranes, organelles, and intracellular signaling pathways. For example, smaller AgNPs (<20 nm) display heightened cellular uptake and ROS production, enabling deeper penetration into cells and targeting mitochondria and the nucleus, while larger particles (>40–50 nm) accumulate in lysosomes, causing lysosomal stress rather than immediate mitochondrial apoptosis (Ejaz et al., 2023). The morphology of AgNPs influences uptake and cellular stress, as spherical forms typically internalize more efficiently than rods or triangles, which can disrupt cell membranes and cytoskeleton. Surface charge, mainly set by the phytochemical corona, guides selective binding to more positively charged cancer cell membranes, facilitating preferential uptake and cytotoxicity; negatively charged AgNPs target malignant cells, while rare positively charged ones, usually protein-capped, can harm both healthy and cancerous cells indiscriminately. The corona, rich in plant-derived compounds, shapes redox properties, ion release, and intracellular fate—phenolic-rich coronas increase ROS and Ag⁺ ion release, amplifying DNA and protein damage, while protein- or polysaccharide-rich coronas slow dissolution and promote distinct death pathways. Ligand chemistry further directs nanoparticle interaction with mitochondrial proteins or DNA, fine-tuning the type and extent of damage. Ultimately, these attribute-dependent mechanisms account for nuanced variations in cytotoxicity, mitochondrial disruption, oxidative bursts, and suppression of DNA repair in oral cancer cells, making the biological impacts of AgNPs emergent behaviors dictated by their unique physicochemical identities rather than universal modes of action (Balu et al., 2022; David et al., 2022; Padmanabhan et al., 2022).

Inbakandan et al. (2016) pioneered the ultrasonic-assisted biosynthesis of AgNPs using Haliclona exigua marine sponge extract, yielding unique flower-like nanocolloids (100–120 nm). These nanoparticles demonstrated potent antibacterial action against oral pathogens (S. aureus, Streptococcus mitis) and selective cytotoxicity toward KB oral cancer cells (IC₅₀: 0.6 μg/mL), outperforming chemically synthesized counterparts. The enhanced bioactivity was attributed to phytochemical capping (terpenoids, alkaloids) and nanoscale surface interactions, which amplified ROS generation and membrane permeabilization in malignant cells (Inbakandan et al., 2016).

Ganesan A. et al. (2024) harnessed Solanum trilobatum leaf extract to synthesize spherical AgNPs (20 nm) stabilized by polyphenolic ligands. These nanoparticles suppressed OSCC proliferation by downregulating PI3K/Akt/mTOR signaling, evidenced by reduced phosphorylated Akt levels and mitochondrial depolarization. DNA laddering assays confirmed apoptosis induction, while negligible cytotoxicity in non-malignant cells highlighted their therapeutic window (Figure 2). The study positions plant-capped AgNPs as dual-targeting agents capable of bypassing chemoresistance mechanisms in oral oncology (Ganesan A. et al., 2024). AgNPs co-opt both mitochondrial (intrinsic) and death receptor (extrinsic) apoptosis pathways. Intrinsic activation involves cytochrome c-mediated caspase-9 signaling, while extrinsic triggers engage cell surface receptors (e.g., Fas, TNF-R1), activating caspase-8. Cross-talk between these pathways via Bid protein cleavage ensures robust apoptosis execution, circumventing cancer cell evasion tactics. Such dual-pathway engagement underscores AgNPs’ versatility in overcoming therapeutic resistance (Loppnow et al., 2013).

Figure 2

Figure 2. Molecular mechanisms underlying the anticancer potential of biogenic AgNPs in oral malignancies.

4.2.1 Oxidative stress and ROS generation

One of the most extensively documented mechanisms of AgNP cytotoxicity is the induction of oxidative stress. Upon internalization, AgNPs generate reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide, and hydroxyl radicals. These ROS overwhelm the antioxidant defenses of cancer cells, including glutathione (GSH), superoxide dismutase (SOD), and catalase. The imbalance between ROS production and antioxidant capacity disrupts cellular redox homeostasis, driving oxidative stress that is toxic to cells (Liao et al., 2023).

The consequences of ROS overproduction are multifaceted. Lipid membranes undergo peroxidation, compromising barrier integrity and altering fluidity. Proteins suffer oxidative modifications that impair enzymatic activity and structural stability. DNA is particularly vulnerable, as oxidative lesions such as eight-oxoguanine accumulate, leading to replication errors and genomic instability. The cumulative damage from these processes destabilizes vital cellular structures and functions, ultimately pushing cells toward programmed or unprogrammed cell death (Ali et al., 2023).

Interestingly, the tumor selectivity of AgNPs is partly attributable to oxidative stress. Cancer cells are characterized by high metabolic activity and elevated basal ROS levels, which make them more dependent on fragile antioxidant systems. When additional ROS are introduced by AgNPs, malignant cells rapidly exceed their oxidative tolerance thresholds. Normal cells, by contrast, typically maintain stronger antioxidant buffering capacity, allowing them to better withstand oxidative insults. This selective vulnerability underpins the therapeutic window of AgNPs in oral cancer therapy. Yang et al. (2023) demonstrated these mechanisms using AgNPs synthesized with Matricaria chamomilla extract. Characterization via UV-Vis spectroscopy, FTIR, and electron microscopy confirmed nanoparticle stability, while DPPH assays revealed potent antioxidant properties. In vitro cytotoxicity assays on oral squamous cell carcinoma (OSCC) lines (HSC-4, Ca9-22, HSC-3) showed dose-dependent cell viability reduction, with HSC-3 cells exhibiting highest sensitivity. This study underscores the dual role of green-synthesized AgNPs as both ROS inducers and selective anticancer agents, leveraging oxidative vulnerability in cancer cells while sparing healthy tissues (Yang et al., 2023).

4.2.2 Mitochondrial dysfunction and intrinsic apoptosis

Mitochondria are central regulators of apoptosis, and AgNPs disrupt their function profoundly. ROS generated by AgNPs directly target mitochondrial membranes, causing depolarization of the mitochondrial transmembrane potential (ΔΨm). This collapse of membrane potential compromises ATP production and initiates a cascade of apoptotic events.

A key consequence of mitochondrial destabilization is the release of cytochrome c into the cytosol. Once released, cytochrome c interacts with apoptotic protease activating factor-1 (Apaf-1) to assemble the apoptosome complex. This complex recruits and activates caspase-9, which then cleaves executioner caspases such as caspase-3 and caspase-7. These proteases orchestrate the controlled dismantling of the cell through DNA fragmentation, chromatin condensation, and membrane blebbing (Elmetwalli et al., 2024; Imath et al., 2024; Nainangu et al., 2024; Saritha et al., 2024; Sivalingam and Pandian, 2024).

The intrinsic apoptotic pathway mediated by mitochondria is often dysregulated in cancer cells, enabling them to evade normal death signals. However, AgNP-induced mitochondrial dysfunction bypasses many of these protective adaptations. By directly collapsing mitochondrial potential and overwhelming redox balance, AgNPs effectively disable cellular survival mechanisms. Importantly, plant-mediated synthesis of AgNPs has been shown to improve their selectivity, as phytochemical capping reduces collateral damage to normal cells while maintaining their mitochondrial toxicity against tumor cells (Gomathi et al., 2020; Ashique et al., 2022; Garapati et al., 2022).

4.2.3 Death receptor activation and extrinsic apoptosis

In addition to targeting mitochondria, AgNPs also activate the extrinsic apoptotic pathway (Yuan et al., 2017). This pathway is initiated at the plasma membrane through the engagement of death receptors such as Fas (CD95) and TRAIL receptors. Binding of ligands or nanoparticle-mediated activation recruits adaptor proteins to form the death-inducing signaling complex (DISC) (Palanisamy et al., 2023; Ghobadi et al., 2024; Mohammed et al., 2024).

The DISC activates caspase-8, which has two distinct roles in apoptosis induction. First, caspase-8 directly activates executioner caspases like caspase-3, initiating apoptosis independently of mitochondria. Second, caspase-8 cleaves Bid into truncated Bid (tBid), which translocates to the mitochondria. This amplifies intrinsic apoptotic signaling by promoting cytochrome c release, thereby linking extrinsic and intrinsic pathways (Devendrapandi et al., 2023; Senthil and Çakır, 2024; Senthilkumaran, 2024). This dual engagement of apoptosis pathways is a key advantage of AgNPs. Cancer cells frequently acquire resistance by disabling one apoptotic route, such as mitochondrial apoptosis, through overexpression of anti-apoptotic proteins like Bcl-2 (Feng et al., 2021). However, by activating both intrinsic and extrinsic pathways, AgNPs ensure redundancy in cell death signaling. Even if one mechanism is blocked, the other remains functional, reducing the likelihood of therapeutic resistance and improving treatment robustness (Do et al., 2025).

A 2016 study by Bhakya et al. demonstrated the apoptotic effects of AgNPs synthesized using Helicteres isora stem bark extract. The nanoparticles (mean size: ∼25.55 nm) exhibited robust antioxidant and antimicrobial activity. Notably, they induced oxidative stress and apoptosis in KB oral carcinoma cells, achieving an IC₅₀ of 70 μg/mL. This study highlights the dual functionality of plant-derived AgNPs, combining therapeutic efficacy with eco-friendly synthesis methods (Bhakya et al., 2016).

Similarly, Subramanyam et al. (2021) synthesized AgNPs using Argyreia nervosa leaf extract, yielding nanoparticles (10–55 nm) with a surface plasmon resonance peak at 421 nm. These AgNPs induced G2/M phase cell cycle arrest and activated caspase-3 in KB oral cancer cells, achieving an IC50 of 58.64 μg/mL. The nanoparticles’ ability to trigger intrinsic apoptosis via mitochondrial disruption underscores their potential as targeted anticancer agents (Subramanyam et al., 2021).

Yakop et al. (2018) synthesized AgNPs using Clinacanthus nutans extract (AgNps-CN) and tested their efficacy on HSC-4 oral squamous cell carcinoma. The nanoparticles demonstrated selective cytotoxicity, with an IC₅₀ of 1.61 μg/mL against cancer cells and no toxicity to normal cells. Apoptosis was confirmed via chromatin condensation and an elevated Bax/Bcl-2 ratio, indicative of intrinsic pathway activation. This study underscores the tumor-selective action of biogenic AgNPs, minimizing off-target harm (Yakop et al., 2018).

4.2.4 DNA damage and inhibition of repair mechanisms

Another major avenue of AgNP cytotoxicity is the induction of DNA damage. AgNPs physically interact with nuclear DNA, causing structural disruptions such as single- and double-strand breaks, crosslinking, and base modifications. At the same time, ROS generated by AgNPs create oxidative DNA lesions, with eight-oxoguanine being the most prominent. This lesion promotes mismatched base pairing during replication, driving mutagenesis and chromosomal instability (Yakop et al., 2018).

Beyond inducing DNA lesions, AgNPs impair the very systems that cancer cells rely on for repair. They inhibit base excision repair (BER), the pathway responsible for fixing small base modifications, and nucleotide excision repair (NER), which resolves bulky DNA adducts. AgNPs also interfere with double-strand break repair pathways, including homologous recombination (HR) and non-homologous end joining (NHEJ) (Waktole, 2023).

By simultaneously inflicting DNA damage and crippling repair machinery, AgNPs create a scenario of irreparable genomic instability. Cancer cells, already characterized by unstable genomes, are pushed beyond their threshold of tolerance. Persistent DNA damage triggers checkpoint activation through kinases such as ATM and ATR, leading to cell cycle arrest. However, if the damage is overwhelming and repair pathways are incapacitated, apoptosis or necroptosis ensues. This dual mechanism of action—damage plus repair inhibition—gives AgNPs a significant therapeutic edge (Quevedo et al., 2021).

4.2.5 Modulation of pro-survival signaling pathways

AgNPs further potentiate their anticancer effects by disrupting signaling cascades that regulate cell survival and proliferation. A critical target is the PI3K/Akt/mTOR pathway, which is frequently hyperactivated in oral squamous cell carcinoma (OSCC). This pathway promotes growth, metabolism, and survival, while also conferring resistance to apoptosis (Huff et al., 2021).

AgNPs suppress the phosphorylation of Akt, effectively shutting down downstream signaling events. This inhibition reduces the expression of anti-apoptotic proteins such as Bcl-2 and prevents the activation of transcription factors like NF-κB. As a result, tumor cells lose proliferative drive and become more sensitive to apoptosis. In addition to PI3K/Akt/mTOR inhibition, AgNPs impact MAPK and JAK/STAT pathways, further curtailing proliferation and inflammatory signaling. By targeting multiple signaling axes simultaneously, AgNPs undermine the adaptive capacity of oral cancer cells. This polypharmacological approach stands in contrast to conventional chemotherapeutics, which typically target single molecules and are therefore more susceptible to resistance development (Liao et al., 2023).

4.2.6 Anti-inflammatory effects

The tumor microenvironment is heavily shaped by chronic inflammation, which fosters carcinogenesis, progression, and metastasis. AgNPs have been shown to exert potent anti-inflammatory effects that complement their direct cytotoxicity (Muhammad et al., 2023). One mechanism involves the suppression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. By lowering the levels of these mediators, AgNPs reduce inflammatory signaling that otherwise promotes tumor survival and angiogenesis (Nayal et al., 2024). AgNPs also inhibit the activation of NF-κB, a master regulator of inflammation and oncogenic transcription. By blocking NF-κB nuclear translocation, AgNPs prevent the expression of genes involved in inflammation, proliferation, and resistance (Sousa et al., 2022).

In addition, AgNPs downregulate the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), two enzymes closely linked to tumor-promoting inflammation. Suppression of these enzymes reduces prostaglandin synthesis and nitric oxide production, dampening inflammatory cascades (Naseer et al., 2022). AgNPs also activate the PPAR-γ pathway, a nuclear receptor that modulates inflammation and promotes apoptosis. Through this mechanism, AgNPs not only suppress inflammation but also enhance tumor cell death (Carvalho-Silva and Dos Reis, 2024).

4.3 Comparison with conventional chemotherapeutic agents

The evaluation of biogenic AgNPs against conventional chemotherapy highlights their potential as alternative or adjunct therapies for oral cancer. Traditional chemotherapeutic agents, though effective in targeting malignant cells, are frequently associated with adverse effects and the emergence of resistance. In contrast, biogenic AgNPs present advantages in efficacy, specificity, and safety, positioning them as a promising therapeutic innovation (Zhou et al., 2025).

Research indicates that AgNPs exhibit cytotoxic effects on oral cancer cells equal to or exceeding those of standard chemotherapeutics. Notably, AgNPs induce apoptosis and reduce viability in cell lines such as SCC-4, SCC-9, CAL 27, and KB, often at lower concentrations than conventional drugs. This heightened potency could minimize dosage requirements and mitigate side effects in clinical applications (Subramanyam et al., 2021; Shukla and Senapathya, 2025).

A 2022 investigation by Halkai et al. examined AgNPs synthesized using Fusarium semitectum fungi, assessing their impact on oral squamous cell carcinoma (SCC-9) via MTT assays. The study revealed concentration-dependent suppression of SCC-9 proliferation, with an IC50 of 12 μL/mL. At 50 μL/mL, cell growth inhibition reached 88.46%, underscoring robust antitumor activity. These findings align with prior work emphasizing the enhanced biological performance of biosynthesized AgNPs, attributed to targeted mechanisms such as oxidative stress induction and cellular disruption. The study reinforces the viability of fungal-derived AgNPs as therapeutic candidates, advocating for eco-friendly synthesis methods in oncology (Halkai et al., 2022).

Similarly, Ghabban et al. (2022) developed AgNPs using Astragalus spinosus extract, evaluating their antibacterial and cytotoxic properties. The nanoparticles demonstrated strong antimicrobial activity against Streptococcus mutans and Actinomyces viscosus, with MIC and MBC values between 10.6 and 26.6 μg/mL. Mechanistic studies linked this activity to ROS generation and subsequent release of cellular components like nucleic acids. Cytotoxicity assays further revealed selective toxicity toward SCC4 oral cancer cells over NOF18 normal cells, highlighting their potential for targeted therapy. This dual functionality positions plant-derived AgNPs as versatile tools in combating oral pathologies while minimizing harm to healthy tissues (Ghabban et al., 2022).

A key benefit of biogenic AgNPs lies in their tumor-selective targeting, facilitated by the enhanced permeability and retention (EPR) effect. Tumor vasculature’s irregular architecture and compromised lymphatic drainage promote nanoparticle accumulation, while cancer cells’ distinct membrane properties enhance AgNP uptake. This specificity reduces off-target toxicity, addressing a major limitation of conventional therapies that indiscriminately affect healthy tissues (Kovács et al., 2022). Biogenic AgNPs also exhibit a favorable safety profile compared to agents like cisplatin and 5-fluorouracil, which are linked to kidney toxicity, nerve damage, and bone marrow suppression. Preclinical studies suggest plant-synthesized AgNPs display lower toxicity toward non-malignant cells, potentially improving patient tolerance and quality of life during treatment (Nikolova et al., 2023). Furthermore, AgNPs may circumvent chemoresistance mechanisms, such as drug efflux or DNA repair upregulation, through multifaceted actions including ROS generation, mitochondrial dysfunction, and signaling pathway interference. These diverse mechanisms reduce the likelihood of resistance, enhancing therapeutic durability (Do et al., 2025). Biogenic AgNPs represent a viable option for oral cancer therapy, combining potent anticancer activity with selective targeting and reduced toxicity. While preclinical data are encouraging, translational success requires further validation through in vivo studies and clinical trials to establish safety, efficacy, and dosing protocols.

5 In Vivo applications of biogenic silver nanoparticles for oral cancer

5.1 Animal models of oral cancer and in vivo efficacy

In vivo validation is crucial for translating the promising in vitro anticancer effects of biogenic AgNPs into clinical practice. Various animal models have been employed to evaluate their therapeutic efficacy, biodistribution, and safety in oral cancer treatment.

Xenograft Models: Human oral squamous cell carcinoma (OSCC) cells (e.g., SCC-9, CAL 27) implanted subcutaneously or orthotopically into immunocompromised mice serve as prevalent preclinical models (Ren et al., 2024). For instance, Subramanyam et al. (2023) reported that intravenous administration of Byttneria herbacea-derived AgNPs at doses of 10 mg/kg body weight thrice weekly for 21 days significantly reduced tumor volume by approximately 62% compared to untreated controls, without observable systemic toxicity. Histopathological analyses revealed extensive tumor necrosis and apoptosis, confirming antitumor activity (Subramanyam et al., 2023). Similarly, Jadhav et al. (2018) demonstrated that AgNPs biosynthesized using Salacia chinensis bark extract, administered intraperitoneally at 5 mg/kg daily for 2 weeks in SCC xenograft-bearing mice, inhibited tumor growth by 54% and decreased proliferation marker Ki-67 expression, while sparing normal tissue architecture (Jadhav et al., 2018).

Syngeneic and Orthotopic Models: Orthotopic implantation of mouse oral cancer cells into immunocompetent mice offers tumor microenvironment fidelity and immune system engagement (Tinajero-Diaz et al., 2021; Zhou et al., 2025). In one study, AgNPs synthesized from Solanum trilobatum leaf extract were administered intratumorally at 3 mg/kg weekly over 4 weeks, resulting in a 70% tumor volume reduction and enhanced survival rates compared to controls. Immune profiling indicated increased infiltration of cytotoxic T cells, suggesting immunomodulatory benefits (Ganesan A. et al., 2024).

Genetically Engineered Mouse Models (GEMMs): Although less commonly applied to AgNP studies, GEMMs recapitulate spontaneous tumorigenesis. Preliminary findings indicate that chronic oral administration of AgNPs at 2 mg/kg for 8 weeks delayed tumor onset and progression, supporting their chemopreventive potential (Janzadeh et al., 2022).

5.2 Dosage, administration routes, and pharmacokinetics

Understanding the in vivo fate of green-synthesized silver nanoparticles requires more than descriptive summaries of animal experiments; it necessitates an analysis of how nanoparticle size, surface chemistry, corona composition, and dose determine biodistribution, accumulation, clearance, and systemic toxicity. Biodistribution studies using ICP-MS consistently report that biogenic AgNPs exhibit preferential accumulation in the liver and spleen, with hepatic concentrations reaching 3%–8% of the administered dose per Gram of tissue within 24 h. This reflects the dominant role of Kupffer cells in nanoparticle sequestration. Smaller nanoparticles (<20 nm) typically show higher renal accumulation due to enhanced glomerular filtration, while larger AgNPs (>40 nm) accumulate primarily in the liver and spleen due to macrophage-driven uptake. (Haripriyaa and Suthindhiran, 2023).

Tumor accumulation is driven by the enhanced permeability and retention (EPR) effect, with biogenic AgNPs exhibiting 5–10-fold higher tumor uptake relative to chemically capped counterparts, likely due to the presence of hydrophilic phytochemical coronas. Comparative biodistribution analyses show that nanoparticles capped with polyphenolic coronas accumulate more efficiently in tumors but also display altered hepatic retention dynamics due to increased protein binding in circulation (Cai et al., 2023).

Clearance mechanisms of biogenic AgNPs depend strongly on particle size and corona chemistry. Particles smaller than 10 nm are predominantly cleared through renal excretion, with up to 40%–50% of the injected dose detected in urine within 72 h. By contrast, larger nanoparticles undergo hepatobiliary clearance, with fecal elimination representing a major excretion route. Corona composition also modulates clearance: protein-rich coronas slow systemic elimination due to increased opsonization, whereas polyphenol-dense coronas facilitate more rapid clearance and reduced long-term tissue retention (Jain and Bhise, 2025).

Organ-specific toxicity profiles reflect these biodistribution patterns. Hepatic toxicity is most frequently reported, typically emerging at doses above 10–20 mg/kg in mice, and is characterized by elevated ALT/AST levels, mild steatosis, and centrilobular inflammation. Renal toxicity becomes relevant for smaller AgNPs due to their efficient renal filtration, with dose-dependent tubular degeneration reported at higher exposure levels. Splenic accumulation may lead to marginal zone expansion or increased oxidative stress, although these effects are generally mild at pharmacologically relevant doses. These findings are consistent with broader nanotoxicology literature, including ferric oxide nanoparticle studies, which emphasize macrophage sequestration, oxidative stress markers, and organ-specific histopathology as key endpoints for safety assessment (Anwaar et al., 2024b).

Dose–response trends underscore the dual nature of AgNPs as both therapeutic and potentially toxic agents. At lower doses (one to five mg/kg), most biogenic AgNPs exhibit minimal systemic toxicity and demonstrate effective tumor growth suppression in xenograft models. However, doses above 20–30 mg/kg may induce oxidative stress, mitochondrial dysfunction, and inflammatory responses in non-target organs, particularly in the liver and kidney. These outcomes highlight the necessity of carefully optimizing dose regimens based on nanoparticle size, surface chemistry, and corona stability (Khan et al., 2025).

Overall, the pharmacokinetic and biodistribution behavior of green-synthesized AgNPs is shaped by a complex interplay between physicochemical characteristics and biological systems. A critical understanding of these interactions is essential for evaluating therapeutic potential, anticipating systemic impacts, and establishing safe translational pathways.

5.3 Therapeutic efficacy and safety profiles

Efficacy: Multiple in vivo investigations demonstrate that biogenic AgNPs exert dose-dependent tumor growth suppression, apoptosis induction, and metastasis inhibition in oral cancer models (Noga et al., 2023). For example, Alsareii et al. (2022) observed that oral administration of Rhizophora apiculata leaf extract-mediated AgNPs (10 mg/kg daily for 3 weeks) reduced tumor volume by 65%, associated with diminished expression of proliferation markers (PCNA) and enhanced caspase-3 activity. Combining AgNPs with low-dose cisplatin synergistically enhanced tumor regression while reducing cisplatin-associated toxicity (Alsareii et al., 2022).

Safety: Comprehensive toxicity assessments include histopathology of major organs (liver, kidney, heart, spleen), blood biochemical analyses, and hematological profiling. Across studies, biogenic AgNPs exhibit minimal organ toxicity at therapeutic doses (Barua and Buragohain, 2024; Dias et al., 2025). Subramanyam et al. (2023) reported no significant changes in liver enzymes (ALT, AST) or renal markers (creatinine, BUN) in treated mice. Hemolysis and coagulation assays confirmed hemocompatibility. Immunological analyses showed no acute hypersensitivity or immunosuppression (Kah et al., 2023). Long-term exposure studies extending to 90 days report no mortality or severe adverse events but highlight the necessity to monitor for possible bioaccumulation and subtle organ function alterations in chronic use (Noga et al., 2023).

5.4 Limitations and considerations for clinical translation

While promising, challenges remain for clinical translation. Variability in nanoparticle size, shape, and surface chemistry due to green synthesis protocols can affect reproducibility and pharmacodynamics. Scaling up production with stringent quality control is essential (Teh et al., 2024). Animal models, especially immunocompromised xenografts, do not fully replicate human immune-tumor interactions. Thus, synergy effects and immunomodulation require validation in more representative models (Saker et al., 2024). Furthermore, precise dosing regimens, nanoparticle stability in physiological conditions, and potential long-term toxicity—including genotoxicity and environmental impact—necessitate thorough investigation (Kah et al., 2023). Clinical trials must establish standardized protocols for administration routes, dosage, and patient selection based on biomarkers such as tumor receptor expression and HPV status to maximize safety and efficacy (Ahmed et al., 2022; Dias et al., 2025).

6 Biocompatibility and toxicity

6.1 Assessment of biocompatibility

Biocompatibility assessment is crucial for determining whether biogenic AgNPs are compatible with biological systems and can be safely used in medical applications. This process involves several key evaluations to ensure that AgNPs do not cause harmful effects to cells, tissues, or the immune system (Venkatesan et al., 2018).

Cell Viability Assays are critical tools for evaluating the effects of AgNPs on cellular health. These assays often employ in vitro models, including fibroblasts, epithelial cells, and endothelial cells, to analyze nanoparticle-induced cytotoxicity. Common methods such as the MTT, MTS, and Alamar Blue assays quantify cellular metabolic activity, offering insights into the dose-dependent toxicity of AgNPs. By identifying concentrations that balance therapeutic effectiveness with minimal harm, these assays guide the establishment of safe nanoparticle dosing guidelines (Abitha et al., 2019).

A 2023 investigation by Pourhaji et al. examined the eco-friendly synthesis of AgNPs using Lactobacillus acidophilus, a probiotic bacterium, and assessed their anticancer potential against oral squamous cell carcinoma (OSCC) cells. This study reflects the expanding role of nanotechnology in medicine, particularly in oncology. The biosynthesized AgNPs were validated through visual color shifts, UV-Vis spectroscopy, and advanced imaging techniques (TEM/SEM), which confirmed their spherical morphology and average size of 397 nm. Using the MTT assay, the researchers observed a concentration-dependent reduction in OSCC cell survival, underscoring the nanoparticles’ therapeutic promise for oral cancer. This work aligns with broader research on green synthesis methods, such as those utilizing plant extracts, which prioritize eco-conscious and biocompatible synthesis techniques. While Pourhaji et al. focused on bacterial synthesis, their findings resonate with plant-based approaches by emphasizing reduced environmental impact and enhanced biocompatibility. Both strategies aim to advance oral cancer treatment by developing safer, more effective AgNP-based therapies (Pourhaji et al., 2023). The integration of such sustainable methods highlights their potential to revolutionize oncology, offering alternatives to conventional, often toxic, cancer treatments.

Hemocompatibility studies are essential for understanding how AgNPs interact with blood components. Blood compatibility assays focus on various aspects, including the potential for hemolysis, which is the lysis of red blood cells (RBCs). Hemolysis assays test whether AgNPs cause RBC rupture, which can lead to adverse reactions in the bloodstream. Additionally, clotting assays are conducted to evaluate the impact of AgNPs on blood coagulation, ensuring that they do not interfere with normal clotting processes and cause unwanted bleeding or clotting disorders (Adhikari et al., 2019; Shravan Kumar and Thangavelu, 2019; Vignesh et al., 2019).

Immunological Compatibility is another critical aspect of biocompatibility assessment. This involves studying the effects of AgNPs on immune cells such as macrophages, dendritic cells, and lymphocytes. Researchers examine cytokine secretion profiles, phagocytosis activities, and immune cell activation to ensure that AgNPs do not elicit adverse immune responses. By evaluating these parameters, it is possible to confirm that AgNPs do not trigger hypersensitivity reactions, excessive inflammation, or other immune system disturbances (Chithralekha and Rajeshkumar, 2019).

Overall, a comprehensive biocompatibility assessment involves these multiple approaches to ensure that AgNPs are safe for use in medical applications. By carefully evaluating cell viability, hemocompatibility, and immunological compatibility, researchers can ensure that AgNPs do not pose significant risks to human health and can be utilized effectively in various therapeutic contexts. This thorough evaluation is critical for the successful translation of AgNPs from preclinical research to clinical use, ensuring they provide beneficial effects without causing harm.

6.2 Potential toxicity to normal cells

While biogenic AgNPs are recognized for their potent cytotoxic effects against cancer cells, it is crucial to thoroughly evaluate their potential toxicity to normal cells to ensure their safe application in clinical settings. Assessing selective toxicity is a primary focus, aiming to determine how preferentially AgNPs target cancer cells compared to normal cells. This is achieved by comparing cytotoxicity profiles across various cancer and normal cell lines, allowing researchers to identify AgNPs that exhibit favorable selectivity indices. Selective toxicity is desirable as it implies that the nanoparticles can effectively target and kill cancer cells while minimizing harm to healthy cells (Ramzan et al., 2022).

In addition to selective toxicity, researchers must address non-specific toxicity, which involves understanding how AgNPs might impact normal cells through unintended mechanisms. AgNPs promote oxidative stress through the generation of ROS, which disrupt critical cellular structures such as DNA, proteins, and lipids. This oxidative damage can result in apoptosis or functional impairment, even in healthy cells. To evaluate such non-selective toxicity, researchers analyze alterations in cell shape, survival rates, and biological activity following AgNP exposure. These assessments help determine the balance between therapeutic benefits and unintended harm, guiding the development of safer nanoparticle-based treatments. Such evaluations are essential for identifying any adverse effects that might arise from exposure to AgNPs (Gayathri et al., 2019).

Organ-specific toxicity is another critical area of concern. To evaluate how AgNPs may affect specific organs, researchers use organotypic models or ex vivo organ culture systems. These models allow for the study of AgNPs’ impact on vital organs like the liver, kidneys, lungs, and brain, providing insights into potential organ-specific responses. For instance, the liver and kidneys are critical for metabolizing and excreting nanoparticles, making them particularly relevant for toxicity studies. Similarly, assessing the effects on lungs and brain helps determine if AgNPs might pose risks in these sensitive areas (Suresh et al., 2019).

Overall, a comprehensive evaluation of AgNPs’ potential toxicity to normal cells involves understanding both their selective and non-selective effects, as well as their impact on specific organs. This thorough approach is essential for ensuring that AgNPs can be safely used in therapeutic contexts without causing significant harm to normal tissues, thus paving the way for their successful clinical application.

6.3 Long-term safety considerations

Long-term experimental studies in animal models have provided critical insights into the potential risks associated with chronic exposure to AgNPs, including those of biogenic origin. Rather than relying on speculation, recent evidence delineates the mechanistic pathways through which such exposures could lead to adverse effects involving genotoxic, neurotoxic, and hepatotoxic outcomes (Sati et al., 2025).

Genotoxicity: Multiple in vivo studies confirm that prolonged oral or parenteral exposure to AgNPs induces significant genotoxic effects in mammals. In Sprague-Dawley rats, for example, repeated oral administration of AgNPs at doses ranging from 5 to 100 mg/kg/day over 5 days resulted in substantial DNA damage in bone marrow cells, increased chromosomal aberrations, heightened micronuclei frequency, and reduced mitotic index. Mechanistically, these effects correlate with an upsurge of reactive oxygen species (ROS), initiating oxidative stress and directly damaging genomic DNA. Review analyses consistently demonstrate that AgNPs produce genotoxic effects at all examined endpoints, including in vivo micronucleus formation, chromosome aberration, and comet assays in mammals. The extent of DNA damage is influenced by nanoparticle characteristics (size, coating), but genotoxicity persists across both biogenic and chemically synthesized AgNPs (Patlolla et al., 2015; Rodriguez-Garraus et al., 2020).

Neurotoxicity: Long-term AgNP exposure has also been implicated in neurotoxicity, predominantly following chronic oral or intravenous administration. In a rigorously controlled mouse study, daily oral dosing with polyvinylpyrrolidone (PVP)-coated AgNPs over 30, 60, 120, and 180 days led to a cumulative, region-specific accumulation of silver in brain tissues—most notably in the hippocampus, cortex, and cerebellum (Wang et al., 2023). Histopathological analysis revealed loss and degeneration of hippocampal CA2 neurons after 120–180 days, which was not observed in other brain regions. Functionally, exposed animals developed impaired social interaction, reduced exploratory activity, and memory deficits, correlating with neuronal injury and disruption of memory-associated structures. Mechanistically, AgNPs cross the blood–brain barrier, provoke persistent oxidative stress, disrupt neuronal integrity, and impair synaptic signaling, collectively resulting in behavioral changes and long-term memory impairment (Wang et al., 2023).

Hepatotoxicity: Persistent AgNP exposure can lead to pronounced hepatotoxicity in animal models. In studies with Sprague Dawley rats, daily intraperitoneal injections of AgNPs at 0.25–1 mg/kg over 15 or 30 days produced dose- and time-dependent liver damage. Documented effects included reduced body and organ weights, elevated serum markers of hepatic injury, and characteristic histopathological lesions—such as cholangiopathy, hepatocellular necrosis, sinusoidal congestion, and Ito cell proliferation. Mechanistically, AgNP-induced hepatotoxicity is mediated by two pathways; Oxidative Stress and Apoptosis: Increased ROS and nitrosative stress deplete glutathione (GSH), upregulate pro-apoptotic factors (BAX, caspase-3), and suppress anti-apoptotic markers (Bcl-2), leading to mitochondrial dysfunction and extensive hepatocyte apoptosis. Fibrosis and Inflammation: Chronic exposure enhances expression of fibrogenic (TGF-β1, α-SMA) and pro-inflammatory (iNOS) genes, activating stellate cells and triggering hepatic fibrosis. Repeated findings confirm these mechanisms are consistent regardless of nanoparticle synthesis route, affirming that biogenic AgNPs also warrant careful, long-term toxicological evaluation (Assar et al., 2022).

7 Challenges

Transitioning biogenic AgNPs from laboratory settings to clinical applications presents significant scale-up hurdles. A primary challenge lies in standardizing production processes, as variations in plant-derived extracts, synthesis parameters, and nanoparticle properties can lead to inconsistencies in size, shape, and bioactivity. Establishing uniform protocols for raw material sourcing, reaction conditions, and quality control is critical to ensure reproducible outcomes across manufacturing batches (Tabasum et al., 2025). Additionally, optimizing production yields without compromising nanoparticle quality remains essential for cost-effectiveness. This requires refining synthesis parameters, such as temperature, pH, and reactant ratios, alongside innovations in reactor design to enhance efficiency. Equally important is streamlining upstream processes, including plant extract preparation, and downstream steps like purification and sterilization (Reshi et al., 2025). Integrating automation and advanced filtration technologies could mitigate bottlenecks, ensuring scalable and sustainable manufacturing (Teh et al., 2024).

7.1 Technical barriers to scalability of biogenic AgNPs

Scalable and clinically compliant production of green-synthesized silver nanoparticles presents significant technical challenges that extend far beyond the conceptual advantages of sustainability and biocompatibility. The primary barrier lies in the intrinsic phytochemical variability of plant extracts, which is influenced by species, geographic origin, season, soil composition, plant age, extraction solvent, and environmental stress conditions (Kordasht et al., 2025). These variations profoundly affect the concentration of key reducing and stabilizing metabolites, including polyphenols, flavonoids, terpenoids, proteins, and organic acids. As a result, nucleation rates, particle size distribution, surface charge, corona composition, and ultimately the biological activity of AgNPs may differ substantially between batches. Achieving clinical-grade reproducibility therefore requires standardized cultivation or controlled sourcing of plant material, quantitative phytochemical fingerprinting (e.g., HPLC, LC–MS), and the establishment of validated extract specifications before synthesis (Muslim et al., 2025).

Purification represents another major technical bottleneck in GMP manufacturing. Plant-mediated reactions introduce complex organic residues, unbound phytochemicals, polysaccharides, and protein fragments that must be removed to meet regulatory purity standards. Laboratory-scale purification using centrifugation or simple washing steps is insufficient for medical applications. GMP-grade workflows require scalable purification technologies such as tangential flow filtration (TFF), membrane ultrafiltration/diafiltration, chromatographic fractionation, and sterile 0.22 µm filtration to ensure consistent removal of organic contaminants. In addition, plant-derived endotoxins and microbial by-products pose safety risks; thus, validated endotoxin quantification using LAL or recombinant Factor C assays is essential for intravenous or intratumoral applications (Guleria et al., 2022).

Reproducibility across manufacturing batches must be verified through comprehensive analytical characterization. This includes particle size and charge (DLS, TEM, NTA, zeta potential), corona chemical composition (FTIR, LC–MS), residual solvent or impurity analysis, and batch-release specifications similar to those used for biologics and nanomedicines. Studies on biogenic copper oxide nanoparticles have demonstrated that synthesis chemistry and purity directly influence biological activity and toxicity profiles; similar consistency must be demonstrated for biogenic AgNPs before clinical progression (Anwaar et al., 2024a).

7.2 Technical barriers to standardization

Long-term stability and shelf-life are additional critical considerations, as green-synthesized nanoparticles are highly sensitive to oxidation, agglomeration, and corona degradation. The phytochemical corona may undergo desorption, denaturation, or oxidation during storage, altering colloidal stability and bioactivity. Stability-indicating assays under ICH Q1A (R2) guidelines—including accelerated stability testing, freeze–thaw assessment, oxidative stress testing, and long-term storage evaluation—are required to determine appropriate storage conditions and validate shelf-life. Stabilization strategies such as cryoprotectants, antioxidant additives, lyophilization, or PEGylation may be necessary to maintain physicochemical integrity during extended storage (Abegunde et al., 2024).

7.3 Technical barriers to GMP translation

Finally, GMP translation demands rigorous documentation, validated standard operating procedures, and compliance with regulatory frameworks such as ICH Q8/Q9, FDA nanomaterial guidelines, and EMA reflection papers. These include critical quality attributes (CQAs), critical process parameters (CPPs), continuous process monitoring, and risk-based quality assessment. Without these layers of standardization and documentation, green-synthesized AgNPs cannot meet clinical or commercial manufacturing requirements (Edo et al., 2025).

Incorporating AgNPs into conventional cancer therapies offers opportunities to enhance treatment efficacy but requires careful strategy. Combining AgNPs with chemotherapy, radiotherapy, or immunotherapy could exploit synergistic mechanisms—for example, sensitizing drug-resistant tumors or amplifying immune responses through antimicrobial effects (Kailasa et al., 2019). However, optimizing combination regimens demands precision in dosing schedules, administration routes, and patient-specific factors to minimize off-target effects. Personalized approaches, guided by biomarkers linked to tumor genetics or nanoparticle uptake efficiency, could refine patient selection (Tabasum et al., 2022). Real-time monitoring via imaging or liquid biopsies may further enable adaptive treatment adjustments. Challenges such as potential interactions with systemic therapies or long-term toxicity necessitate meticulous preclinical validation to ensure compatibility and safety (Ren et al., 2024).

Overcoming manufacturing, regulatory, and integration challenges is pivotal to unlocking the potential of biogenic AgNPs for oral cancer therapy. While scalability and compliance hurdles persist, advancements in synthesis techniques, combinatorial strategies, and personalized medicine offer promising avenues. By prioritizing interdisciplinary collaboration and innovative research, AgNPs may emerge as a versatile and effective component of future cancer treatment paradigms, addressing unmet needs in precision oncology.

8 Future research directions

Advancing biogenic AgNPs for oral cancer therapy requires focused efforts on several key fronts. First, well-designed clinical trials are essential to establish safety, optimal dosing, and therapeutic efficacy in diverse patient populations (Jangid et al., 2024). These trials should incorporate standardized protocols and biomarker-driven patient stratification to enhance reproducibility and outcome precision (Mushtaq and Rohit, 2025). Second, innovative nanoformulation strategies—such as ligand-functionalized, stimuli-responsive, or biodegradable carriers—can improve targeted delivery, controlled release, and minimize off-target effects (Singh et al., 2025). These formulations may leverage tumor-specific features like acidic microenvironments or overexpressed receptors to maximize therapeutic index. Third, personalized AgNP therapy guided by tumor genotyping and molecular profiling can tailor treatment based on individual tumor characteristics, including genetic mutations, receptor expression, and resistance mechanisms (Elechi et al., 2025). Integrating precision medicine approaches with nanoparticle design holds promise for overcoming therapeutic resistance and maximizing clinical benefit. Collectively, these future directions aim to translate green-synthesized AgNPs from experimental agents into effective, customized oral cancer treatments with improved patient outcomes (Dey et al., 2022).

9 Conclusion

Biogenic AgNPs synthesized through plant extract-mediated green synthesis present a promising approach for advancing oral cancer therapy. Their unique physicochemical properties and eco-friendly synthesis offer notable advantages over traditional treatments. This review underscores the progress made in understanding AgNPs’ synthesis, characterization, and therapeutic potential, including their mechanisms of action such as apoptosis induction, ROS generation, DNA damage, and anti-inflammatory effects. These nanoparticles demonstrate potent cytotoxicity against oral cancer cells while showing favorable biocompatibility and minimal toxicity to normal cells. However, challenges such as scale-up, manufacturing, and regulatory issues must be addressed for clinical application. Future research should focus on enhanced formulations, detailed mechanistic studies, clinical trials, and multidisciplinary collaboration to fully realize AgNPs’ potential in oral cancer therapy. Biogenic AgNPs, with continued innovation and research, could significantly enhance cancer treatment and improve patient outcomes.

Author contributions

RK: Resources, Conceptualization, Validation, Investigation, Formal Analysis, Writing – original draft, Data curation. PN: Data curation, Formal Analysis, Conceptualization, Resources, Writing – original draft, Investigation. IsM: Resources, Validation, Data curation, Writing – review and editing, Investigation. MB: Investigation, Writing – review and editing, Resources, Validation, Data curation. SS: Resources, Validation, Writing – review and editing, Data curation, Investigation. DP: Writing – review and editing, Resources, Investigation, Validation, Data curation. KR: Data curation, Validation, Writing – review and editing, Investigation, Conceptualization, Resources. MM: Project administration, Formal Analysis, Validation, Resources, Data curation, Conceptualization, Supervision, Writing – review and editing, Investigation, Funding acquisition. IoM: Resources, Conceptualization, Validation, Visualization, Project administration, Formal Analysis, Data curation, Investigation, Writing – review and editing, Supervision, Funding acquisition.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was funded by Lucian Blaga University of Sibiu and Hasso Plattner Foundation research grants LBUS-IRG-2022-08.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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