The controlled release of drugs from nanoparticles is essential for maintaining therapeutic concentrations over time, especially for agents with limited stability in physiological environments. Polymeric carriers like PLGA protect drugs from premature degradation, ensuring active compounds remain potent until reaching the target site (Gupta et al., 2018). However, achieving sustained release without compromising stability remains challenging. Rapid polymer degradation may trigger premature release and reduce tumor-site retention, whereas slower degradation can delay therapeutic action.

The stability and clearance of nanoparticles in the bloodstream are significantly affected by immune recognition, which can lead to rapid elimination and reduced circulation time (Tian et al., 2022). To address this, PEGylation (polyethylene glycol conjugation) to the nanoparticle surface, is widely employed. This hydrophilic coating helps shield nanoparticles from immune detection, prolonging systemic circulation. Numerous studies have shown that PEGylation reduces immune uptake, enhancing nanoparticle stability and half-life. However, emerging evidence indicates that PEGylation may impair nanoparticle internalization by tumor cells, potentially limiting therapeutic efficacy (Suk et al., 2016). This has prompted the development of advanced delivery systems capable of responding to tumor microenvironmental cues, such as pH or enzymatic activity, to trigger drug release selectively at the tumor site. (Kang et al., 2020).

Ensuring nanoparticle stability in the bloodstream is critical for systemic administration, particularly in advanced or metastatic OSCC. Polymeric nanoparticles must circulate sufficiently to reach the tumor and accumulate via mechanisms such as the EPR effect or active targeting (Vagena et al., 2025). As alternatives to PEGylation, zwitterionic polymers are being explored for their ability to reduce immunogenicity and minimize interactions with plasma proteins that may provoke immune responses. Recent studies highlight their potential to enhance bioavailability and improve targeting selectivity in tumor therapy (Zheng N. et al., 2019; Peng et al., 2020).

The EPR effect is a key mechanism in nanoparticle-based drug delivery, enabling preferential accumulation in solid tumors due to their leaky vasculature and poor lymphatic drainage. While this effect supports targeted delivery in many cancers, its efficacy in OSCC is hindered by the dense, fibrotic extracellular matrix (ECM), which restricts nanoparticle penetration and limits the full therapeutic potential of EPR-mediated accumulation (Shi et al., 2020).

Recent developments in nanoparticle design aim to overcome the limitations posed by the dense ECM in OSCC by modifying surface properties such as charge and hydrophilicity to improve tissue penetration (Cahn et al., 2024). These changes enhance nanoparticle diffusion through the tumor interstitium, increasing the likelihood of reaching cancer cells. Additionally, functionalization with enzymes like collagenase has proven effective in degrading ECM components, allowing deeper tumor infiltration without harming adjacent healthy tissues. This dual approach—surface modification and enzymatic degradation—significantly improves drug distribution and therapeutic outcomes (Chen M. et al., 2023). Enhancing nanoparticle penetration through the fibrotic OSCC ECM is essential to complement the passive targeting achieved by the EPR effect.

Despite these advancements, a major challenge remains the variability of the EPR effect across different patients due to tumor heterogeneity. The EPR effect is not uniform across all tumors or patients, as variations in vascular permeability, ECM composition, and other microenvironmental factors can significantly impact nanoparticle accumulation. This variability underscores the need for more individualized approaches to nanoparticle drug delivery.

To overcome the limitations of the EPR effect in OSCC, researchers are employing combination strategies that integrate passive targeting with active mechanisms. Active targeting involves functionalizing nanoparticles with ligands that bind to receptors overexpressed on tumor cells, enabling more selective drug delivery. By coupling EPR-based accumulation with receptor-mediated targeting, this dual strategy enhances nanoparticle localization and specificity, offering a more effective and tailored approach to drug delivery in OSCC (Kang et al., 2020).

Biodegradable polymers such as PLGA are widely used in DDS due to their excellent biocompatibility, reducing the risk of long-term toxicity and making them suitable for repeated or localized administration in OSCC treatment. This is particularly important for delivery systems applied within the sensitive oral cavity. However, balancing biocompatibility with sustained drug release remains a challenge. Rapid PLGA degradation may compromise drug retention, undermining the prolonged therapeutic effect needed for optimal treatment outcomes.

To overcome the limitations of rapid polymer degradation, dual-polymer systems combining PLGA with polymers like polycaprolactone (PCL) or PEG have been widely explored (Gupta et al., 2018). These combinations enhance drug retention while maintaining biocompatibility and minimizing adverse effects. PEG, in particular, is extensively used for its capacity to prolong circulation time by protecting nanoparticles from immune recognition and clearance. Its utility in long-circulating DDS has made it a staple in nanoparticle engineering. However, growing evidence highlights potential concerns related to PEGylation. Prolonged exposure can induce the formation of anti-PEG antibodies—a phenomenon known as the “PEG dilemma”—which may lead to immune responses, faster nanoparticle clearance, and reduced therapeutic efficacy (Yin et al., 2023). Additionally, PEGylation can influence drug release kinetics, as the PEG shell may act as a barrier, impeding controlled drug diffusion and compromising overall treatment performance.

To address these challenges, alternative strategies such as zwitterionic polymers and hyperbranched polyglycerols (HPGs) are being investigated for their ability to provide prolonged circulation without provoking significant immune responses. These materials exhibit ultralow fouling characteristics, limiting protein adsorption and immune recognition while supporting efficient drug delivery (Deng et al., 2014; Peng et al., 2020). Additionally, stimuli-responsive PEG derivatives that degrade or detach under tumor-specific conditions—such as low pH or enzymatic activity—are being developed to improve site-specific drug release and overcome issues related to conventional PEGylation (Liang et al., 2021). Continued research is essential to refine these dual-polymer and PEG-alternative systems, ensuring the preservation of circulation time and release control while minimizing immunogenicity. This includes elucidating the mechanisms of anti-PEG antibody formation and creating predictive models for long-term safety. Such advances will be critical for fully realizing the therapeutic potential of PLGA-based and hybrid polymeric delivery systems (Duskey et al., 2020).

Active targeting represents a key advancement in nanoparticle-based drug delivery for OSCC, relying on the functionalization of nanoparticles with ligands that bind selectively to receptors overexpressed in tumor cells, such as CD44 and folate receptors. This strategy enhances drug specificity, minimizes systemic toxicity, and reduces off-target effects by directing therapeutic agents to malignant tissues, including both primary and metastatic OSCC lesions.

Hyaluronic acid (HA), a natural CD44 ligand with high affinity and excellent biocompatibility, is among the most studied molecules for this purpose (Diao et al., 2019). Due to the frequent overexpression of CD44 in OSCC, particularly in tumor-initiating cells, HA-functionalized polymeric nanoparticles offer a promising platform. Studies have demonstrated that HA-coated nanoparticles significantly increase cellular uptake in CD44-overexpressing OSCC cells. De Capua et al. (2021) reported a fourfold enhancement in drug accumulation using HA-functionalized nanoparticles compared to non-targeted formulations, leading to improved therapeutic efficacy. Additionally, catechol-functionalized nanoparticles have shown potential for precise CD44 binding and sustained drug release in OSCC models, further supporting the versatility of ligand-mediated targeting approaches (De Capua et al., 2021).

Despite these advances, challenges remain. Receptor saturation and shedding can limit the uptake and binding efficiency of functionalized nanoparticles. To overcome these, dual-targeting systems, such as combining folic acid (FA) with tumor-specific peptides, show promise in addressing receptor heterogeneity and enhancing binding across diverse tumor subpopulations (Yin et al., 2023). This dual-ligand approach provides a synergistic effect, increasing the likelihood of effective binding even in heterogeneous tumors.

Furthermore, stimuli-responsive nanoparticles, particularly pH-sensitive designs, add specificity. The acidic tumor microenvironment (pH ∼ 6.5–6.8) enables targeted drug release, complementing receptor-mediated targeting. Liu et al. (2018) reported that FA-functionalized pH-sensitive nanoparticles increased drug release and doubled tumor cell apoptosis in acidic conditions. Similarly, Chen H. et al. (2020) developed a dual-targeting system combining pH sensitivity and receptor targeting, demonstrating enhanced specificity and efficacy in preclinical OSCC models (Liu et al., 2018; Chen H. et al., 2020). The increasing reports of polymeric nanoparticles for active targeting in OSCC or HNSCC models highlight their translational potential.

PDT, utilizing light-activated nanoparticles loaded with photosensitizers like nano-graphene oxide, shows promise as an adjunct to traditional cancer therapies (Shi et al., 2024). PDT leverages nanoparticles’ ability to generate reactive oxygen species (ROS) upon light exposure, selectively ablating tumor cells while sparing healthy tissues (Shi et al., 2018). However, light penetration into deeper tumor tissues remains a challenge, particularly in less accessible oral cavity regions. Innovations like coatings enhancing light penetration, or combining PDT with immunotherapy, are addressing these limitations. Near-infrared light-responsive nanoparticles also hold significant promise for deep tissue penetration, enabling treatment in challenging anatomical locations (Shi et al., 2018; Yang et al., 2020). Polymeric nanoparticles encapsulating photosensitizers have been explored for OSCC PDT, aiming to improve photosensitizer solubility, stability, and targeted delivery to enhance localized cytotoxic effects while minimizing systemic photosensitivity.

The dense ECM in OSCC tumors significantly hinders effective therapeutic agent delivery. Strategies like functionalizing nanoparticles with ECM-degrading enzymes or designing smaller nanoparticles (less than 100 nm) are being explored to enhance tumor penetration. Recent studies show that nanoparticles modified with ECM-modulating agents significantly improve drug delivery and distribution in preclinical OSCC models (Netti et al., 2000; Chen M. et al., 2023). Specifically, for OSCC, enhancing polymeric nanoparticle penetration through the collagen-rich ECM is critical for achieving therapeutic concentrations throughout the tumor mass. Additionally, combining nanoparticles with ultrasound-activated microbubble technology represents a new strategy to enhance tumor penetration without compromising healthy tissues (Ingram et al., 2020).

While polymeric nanoparticles generally exhibit excellent safety profiles, their functionalization and surface modifications necessitate thorough preclinical evaluation for long-term toxicity. Given the oral mucosa’s sensitivity, comprehensive safety assessments, including local tissue reactions and systemic exposure, are crucial for polymeric DDS targeting OSCC. Future research should focus on developing modular nanoparticles with precise functionalization control to minimize systemic interactions while preserving therapeutic efficacy (Ahmad et al., 2021). Advances in computational modeling could aid in predicting nanoparticle behavior in biological systems, improving safety assessments and expediting safer, more effective therapeutic solutions (Eckmann et al., 2020).

Polymeric nanoparticles hold significant promise for OSCC treatment, offering targeted drug delivery, controlled release, and the potential to integrate multiple therapeutic modalities like active targeting and PDT (Yin et al., 2023). Despite persistent challenges—particularly immune clearance, ECM barriers, and receptor heterogeneity—ongoing nanotechnology advancements are poised to address these, paving the way for clinically viable nanoparticle-based therapies for oral cancer (Netti et al., 2000; Wang et al., 2015). Continuous refinement of nanoparticle design, alongside emerging complementary technologies, holds immense potential to revolutionize OSCC treatment paradigms, ultimately improving patient outcomes and minimizing side effects (Bhattacharya et al., 2023).

Inorganic nanoparticles (e.g., AuNPs, mesoporous silica, magnetic nanoparticles) hold significant promise for enhancing the EPR effect in oral cancer therapy due to their high surface area and functionalization ease (Wang et al., 2017; Zuo et al., 2020). Surface modifications with polymers like PEG and specific ligands optimize tumor accumulation by exploiting both passive EPR and active targeting (Kalimuthu et al., 2018). Functionalization with enzymes such as collagenase helps overcome the dense ECM barrier in OSCC, facilitating deeper nanoparticle penetration. Despite these advancements, challenges like tumor heterogeneity, vasculature variability, and potential toxicity necessitate further refinement (Netti et al., 2000; Liu Xingguang et al., 2022). Harnessing the EPR effect with inorganic nanoparticles is a key passive targeting strategy for OSCC solid tumors, requiring overcoming the dense ECM. Combining EPR-based strategies with receptor-mediated targeting and therapeutic modalities like photothermal therapy can maximize efficacy while minimizing systemic side effects, paving the way for personalized cancer therapies (Li et al., 2023).

Biocompatibility and biodegradability are crucial for the clinical application of inorganic nanoparticles, directly impacting safety and long-term efficacy. Gold nanoparticles, TNTs, and ZnO NPs exhibit high biocompatibility, minimizing adverse effects. However, concerns persist regarding the degradation of these nanoparticles into non-toxic byproducts post-therapy (Asar et al., 2019). Breakdown products, especially for TNTs and ZnO NPs, require careful study to ensure no long-term health risks (Li et al., 2012; Tabrez et al., 2022). For inorganic nanoparticles in OSCC DDS, particularly for local or repeated systemic administration, understanding their long-term fate and the toxicity of degradation products systemically and within the oral cavity is vital. While biodegradable nanoparticles are attractive for reduced long-term toxicity, balancing this with sustained drug release is challenging, as rapid degradation can lead to premature drug release and reduced efficacy. This highlights the need for research into nanoparticles with controlled degradation profiles for sustained release without compromising safety (Li et al., 2012; 2019).

Active targeting with inorganic nanoparticles offers unique advantages due to their physicochemical stability and multifunctional potential, particularly valuable for OSCC treatment. Inorganic nanoparticles like AuNPs can be functionalized with ligands, such as hyaluronic acid, to specifically bind receptors overexpressed on tumor cells (e.g., CD44 in OSCC), enhancing cellular uptake and therapeutic efficacy (Oladimeji et al., 2021). These nanoparticles also offer inherent benefits, including enhanced imaging contrast and photothermal properties, exploitable for integrated diagnostic and therapeutic (theranostic) applications (Bhattacharya, 2022). Despite these attributes, challenges like receptor saturation and shedding persist, potentially limiting targeting efficiency. To overcome this, recent studies propose dual-targeting strategies incorporating multiple ligands to engage a wider array of tumor-specific markers. Furthermore, integrating active targeting with stimuli-responsive mechanisms, such as pH-triggered drug release, refines treatment specificity and precision (Alexander-Bryant et al., 2017; Li et al., 2020; Xu et al., 2023). This innovative combination leverages the distinctive properties of inorganic nanoparticles to advance targeted drug delivery in OSCC.

PDT is an innovative cancer treatment using light-activated photosensitizers to induce cell death. Inorganic nanoparticles, such as AuNPs and TNTs, have been explored as carriers for PDT agents due to their efficient light absorption and conversion capabilities (Essawy et al., 2021; Tang et al., 2023). Recent studies indicate that combining PDT with chemotherapy can yield synergistic effects, improving tumor ablation while minimizing systemic side effects (Zhang Z. et al., 2020). Challenges persist, particularly with light penetration in deeper tumor tissues, a significant issue in the oral cavity due to light attenuation (Miranda-Filho and Bray, 2020). Recent developments in near-infrared light-responsive nanoparticles offer a promising solution for deeper tissue penetration. Further research is necessary to optimize these systems and improve their efficacy in treating deep-seated tumors (Peng et al., 2022). Inorganic nanoparticles are being investigated as photosensitizer carriers for OSCC PDT, offering advantages in localized reactive oxygen species (ROS) generation upon light activation, though optimizing light penetration for deeper oral cavity tumors remains a key challenge (Wang et al., 2024; Zhang et al., 2024).

Stability in the bloodstream is crucial for nanoparticle-based drug delivery. Inorganic nanoparticles like AuNPs and ZnO NPs often face rapid immune clearance, reducing therapeutic efficacy (Kalimuthu et al., 2018). Surface modifications, such as PEGylation, commonly enhance nanoparticle stability and circulation time. However, while PEGylation improves stability, it can also hinder cellular uptake, suggesting a need for more sophisticated approaches to balance stability with effective drug delivery (Tian et al., 2022). Ensuring the stability of inorganic nanoparticles in systemic circulation is important for reaching OSCC tumors, especially for metastatic disease, and strategies like PEGylation are used to prolong their half-life and reduce rapid clearance.

Achieving effective tumor penetration remains a significant challenge for inorganic nanoparticle-based therapies in oral cancer (Li et al., 2020). The compact extracellular matrix (ECM) surrounding OSCC tumors restricts the even distribution and deep infiltration of these particles. Recent investigations indicate that tailoring the nanoparticle surface—by incorporating ECM-degrading enzymes or by reducing particle size—can markedly enhance intra-tumoral dispersion (Yang X.-Y. et al., 2022). Furthermore, adjunctive techniques like ultrasound stimulation and magnetic guidance have shown promise in promoting deeper nanoparticle infiltration (Zhu et al., 2018). Overcoming the dense ECM in OSCC is a major hurdle for inorganic nanoparticle penetration; strategies involving ECM-degrading enzymes or smaller particles are being explored to improve their distribution within oral tumors. Beyond their role in targeted drug delivery, inorganic nanoparticles are also leveraged for their multifunctional capabilities, including photothermal therapy and PDT (Shi et al., 2024). Nevertheless, challenges persist, including overcoming the dense ECM barrier, addressing inter-patient variability, and ensuring long-term biocompatibility and safety. Continued research is vital to optimize these nanoparticle systems, refine their physicochemical properties, and ultimately surmount biological barriers in oral cancer treatment. With sustained innovation and rigorous clinical validation, inorganic nanoparticles could emerge as a pivotal component in personalized therapeutic strategies for oral cancer.

Advances in low-dimensional nanomaterials show rapid progress towards clinical oncology applications. A prominent example is 2D hexagonal boron nitride (h-BN) nanomaterials, or “white graphite.” While less explored than graphene oxide (GO), h-BN exhibits unique properties making it an excellent drug delivery candidate (Emanet et al., 2019). h-BN nanosheets possess exceptional physicochemical properties, including chemical stability, high surface-to-volume ratio, and biocompatibility, making them efficient for targeted delivery of chemotherapeutics to tumor-specific sites (Rasul et al., 2021). For instance, h-BN applications in targeted drug delivery have demonstrated controlled and efficient release in acidic tumor microenvironments, minimizing systemic toxicity (Visani De Luna et al., 2023). This capability underscores its potential as a key material for developing more effective targeted therapies for oral carcinoma, particularly when combined with photodynamic or ROS-based therapies, where synergistic interactions with the tumor environment can amplify therapeutic effects. While still emerging, 2D inorganic nanomaterials like h-BN are being explored as drug carriers in oral cancer, leveraging their unique properties for targeted delivery and potential synergistic effects with other therapies within the OSCC TME.

The EPR effect enables passive targeting of nanoparticles to tumor tissues due to their leaky vasculature. SLNs and NLCs leverage this to localize chemotherapeutic agents within tumors, reducing systemic toxicity. However, tumor heterogeneity, characterized by irregular vascularization and variable interstitial pressure, significantly challenges the EPR effect’s consistency in OSCC. Studies comparing nanoparticle penetration in 2D versus 3D tumor models highlight current in vitro platforms’ limitations in predicting in vivo efficacy (Goodarzi et al., 2021). Dense ECMs in OSCC, for instance, limit nanoparticle diffusion, underscoring the need for ECM-modifying strategies. Proposed approaches include co-delivery of ECM-degrading enzymes, such as collagenase, to improve nanoparticle penetration (Yao et al., 2020). Additionally, emerging technologies like ultrasound-mediated nanoparticle delivery may transiently enhance vascular permeability, augmenting the EPR effect (Ingram et al., 2020). LNPs can leverage the EPR effect for passive accumulation in OSCC tumors, but the dense ECM requires strategies to enhance their penetration for effective drug delivery throughout the tumor.

The biocompatibility and biodegradability of lipid-based nanoparticles are critical for clinical acceptance. Some studies indicate that biodegradable lipid matrices can minimize cytotoxicity, a key concern in oral cancer therapies (Syama et al., 2022; Amiri, Ziaei Chamgordani and Ghourchian, 2024). However, the safety of degradation products, particularly from modified or synthetic lipids, remains insufficiently studied. Long-term studies are needed to assess the immunological and metabolic impacts of lipid degradation products, especially in preclinical models simulating chronic drug administration, given their potential effect on treatment outcomes in patients with compromised metabolic functions (Di et al., 2023; Preeti et al., 2023; Back et al., 2024). For LNP-based DDS in OSCC, ensuring biocompatibility and understanding the fate and potential toxicity of lipid degradation products is essential for patient safety, particularly with local or repeat administration. Additionally, integrating advanced computational models with experimental approaches can predict nanoparticle degradation behavior under physiological conditions (DeLoid et al., 2015; Ramezanpour et al., 2016; Rezić and Somogyi Škoc, 2024).

Active targeting of LNPs involves functionalizing their surfaces with ligands (e.g., folate, peptides, antibodies) that bind to overexpressed receptors in cancer cells (Van Der Meel et al., 2020). For instance, Bhattacharya et al. demonstrated that surface-functionalized LNPs can selectively target oral cancer cells, improving therapeutic efficacy (Bhattacharya, 2022). Similar to polymeric and inorganic nanoparticles, LNPs can be functionalized with ligands or antibodies targeting relevant OSCC receptors like CD44 or EGFR to achieve active targeting and improve therapeutic efficacy. However, receptor downregulation after repeated targeting remains a significant challenge. To address this, developing multifunctional LNPs capable of targeting multiple pathways or receptors simultaneously could improve therapeutic robustness. Biomimetic approaches, such as coating LNPs with cancer cell-derived membranes, may also enhance targeting specificity and reduce receptor downregulation (Gong et al., 2020).

Stimuli-responsive LNPs that release their payloads in response to environmental triggers—such as pH, temperature, or enzymatic activity—have shown promise in preclinical studies (Hirai et al., 2021). For example, SLNs encapsulating paclitaxel exhibited enhanced cytotoxicity and reduced systemic toxicity by preferentially releasing the drug in acidic tumor microenvironments (Khatri et al., 2020). Stimuli-responsive LNPs, particularly those sensitive to the acidic OSCC TME, are being explored to achieve controlled and localized drug release, enhancing efficacy and minimizing systemic side effects. To further improve these systems, integrating real-time monitoring capabilities, such as fluorescent or MRI-active probes, into LNP designs could enable clinicians to dynamically adjust treatment protocols, aligning drug release with the evolving tumor microenvironment and maximizing therapeutic efficacy (Sun et al., 2021).

LNPs face challenges related to aggregation and degradation in systemic circulation, limiting therapeutic efficacy. Coating strategies like PEGylation effectively enhance nanoparticle stability and prolong circulation time (Tian et al., 2022). However, PEGylation’s immunogenicity, particularly the “accelerated blood clearance” phenomenon, remains a concern. Recent studies explore alternative coatings, such as zwitterionic polymers and polysaccharides, offering similar stability benefits without immunogenicity issues (Peng et al., 2020). Personalized nanoparticle formulations, tailored to individual patient immune profiles, could further enhance LNP clinical applicability. Maintaining LNP stability in systemic circulation is crucial for successful delivery to OSCC tumors, especially for metastatic disease, and strategies like PEGylation or alternative coatings are employed to prolong their bloodstream lifespan (Chaudhary et al., 2024).

Efficient penetration of LNPs into oral cancer tissues is critical but challenging due to the dense ECM and tumor heterogeneity. Studies show NLCs loaded with compounds like curcumin can enhance nanoparticle diffusion in tumor spheroids, indicating potential to overcome ECM barriers (Xu et al., 2020). However, the high collagen content and dense fibrotic structure of oral cancer ECM restrict nanoparticle infiltration (Yao et al., 2020). A promising strategy to address this involves co-delivery of ECM-modulating agents, such as collagenase, which selectively degrades the matrix and enhances nanoparticle penetration without harming healthy tissue (Netti et al., 2000).

The TME also significantly influences nanoparticle interaction, with variations in pH, hypoxia, and receptor expression affecting efficiency (Sun et al., 2021). Stimuli-responsive LNPs, which release drugs in response to acidic or hypoxic conditions, are emerging as a promising approach to enhance specificity and minimize off-target effects (Zhu et al., 2019). Tumor heterogeneity further complicates consistent nanoparticle penetration. Recent studies highlight the importance of advanced imaging and computational modeling to predict LNP behavior in vivo and guide the development of more effective, personalized delivery systems (Di et al., 2023). Overcoming the dense OSCC ECM is a major barrier; strategies involving ECM degradation or stimuli-responsiveness based on the TME are being explored to improve LNP distribution within oral tumors. These innovative approaches enable tailoring LNP delivery to overcome complex TME barriers, offering improved oral cancer treatment outcomes.

Although LNPs are generally considered safe, their accumulation in vital organs and the long-term effects of degradation products necessitate thorough investigation (Yang L. et al., 2022). While largely biocompatible, prolonged safety and potential accumulation of LNPs or their degradation products in organs susceptible to systemic exposure in OSCC treatment demand further scrutiny. High-resolution imaging coupled with multi-omics approaches could offer valuable insights into nanoparticle biodistribution and toxicity profiles during extended treatment courses (Di et al., 2023).

The acidic of the TME, driven by the Warburg effect and resulting lactate accumulation, provides a natural trigger for pH-sensitive drug delivery systems (DDS). This allows selective therapeutic agent release at the tumor site, maximizing local drug concentrations while minimizing systemic exposure (Chen H. et al., 2020). The acidic pH (approximately 6.5–6.8) in the OSCC TME makes pH-sensitive nanoparticles highly relevant for targeted drug release in oral cancer.

An example is thermo-pH dual-responsive polymersomes loaded with a poly (N-isopropylacrylamide)-doxorubicin (PNIPAM-DOX) conjugate. These PEG-PTMBPEC polymersomes are stable physiologically but disassemble at acidic tumor pH (<6.5) due to acetal bond degradation. Concurrently, the thermoresponsive hydrogel forms a gel at body temperature, sustaining drug release. This system enhances DOX bioavailability, prolongs circulation, and significantly inhibits tumor growth in vivo, with reduced systemic toxicity compared to free DOX (Oroojalian et al., 2018).

However, tumor heterogeneity, specifically variations in pH across tumor regions and intracellular compartments, poses challenges to consistent pH-sensitive DDS performance, leading to unpredictable drug release. To overcome this, hybrid systems combining pH sensitivity with other triggers like temperature or ROS are being explored to improve specificity and therapeutic consistency (Li et al., 2020). pH-Sensitive polymeric nanoparticles and polymersomes are being investigated for targeted chemotherapeutic delivery to the acidic OSCC tumor site, showing improved efficacy in preclinical models.

Temperature-sensitive DDS exploit TME fluctuations, especially those induced by hyperthermia, to control drug release. Elevated tumor temperatures (42°C–45°C), driven by inflammation, metabolic activity, or external heat, trigger phase transitions in thermosensitive materials. These systems, often hydrogels or nanoparticles, remain liquid at physiological temperatures but undergo a sol-gel transition at elevated temperatures, enabling localized and sustained drug release (Li et al., 2012). Temperature-sensitive nanoparticles can be combined with hyperthermia (e.g., induced by PTT) to trigger localized drug release within OSCC tumors, offering synergistic therapeutic effects.

When combined with hyperthermia-based therapies, temperature-sensitive DDS demonstrate synergistic effects. For instance, thermosensitive hydrogels loaded with DOX and gold nanoparticles have shown enhanced tumor ablation (Li et al., 2016). The photothermal properties of gold nanoparticles amplify localized heating, facilitating precise drug release and improved therapeutic efficacy. Despite their promise, challenges remain in achieving uniform tumor heating and precise phase transition control. Hybrid systems integrating temperature sensitivity with pH or ROS responsiveness are being developed to address these issues, enabling broader clinical applicability (Zhang et al., 2021).

Elevated ROS levels in the TME, driven by hypoxia and rapid cell division, present a promising trigger for DDS. ROS-sensitive systems are designed with linkages, such as thioketal bonds, that undergo oxidative cleavage in response to ROS, ensuring selective drug release at the tumor site (Shi et al., 2018). In OSCC models, ROS-sensitive nanoparticles show great potential. For example, curcumin-loaded nanoparticles release their therapeutic payload in response to elevated ROS levels, enhancing localized drug delivery and reducing systemic toxicity (Zhang Z. et al., 2020). The elevated ROS levels in the hypoxic regions of OSCC tumors provide a relevant stimulus for ROS-sensitive nanoparticles, enabling localized drug release and enhancing therapeutic effects, as demonstrated with systems like curcumin-loaded nanoparticles. However, variability in ROS levels across tumor regions and patients remains a significant challenge. To optimize drug delivery and improve therapeutic precision, real-time imaging of ROS levels integrated with DDS is being explored (Zhang et al., 2021).

A key advantage of exosomes is their exceptional biocompatibility, primarily due to their lipid bilayer structure resembling parent cells. This minimizes immune recognition and inflammatory responses common with synthetic nanoparticles, making exosomes particularly suitable for clinical applications and crucial for reducing systemic toxicity in cancer treatments (Wu et al., 2024). Studies demonstrate that exosomes from various cellular sources exhibit low immunogenicity and prolonged circulation times, enhancing encapsulated drug bioavailability by evading rapid clearance (Bagheri et al., 2020). Furthermore, certain exosomal surface proteins, like CD47, mediate immune evasion, though precise mechanisms remain under investigation (Cheng et al., 2021). Despite these advantages, challenges persist in fully understanding exosome biodistribution and immune system interactions, warranting further research. The high biocompatibility and low immunogenicity of exosomes are particularly attractive for OSCC DDS, potentially leading to better tolerability compared to some synthetic nanocarriers.

Exosomes are inherently equipped with targeting properties conferred by their surface composition, reflecting their parent cells’ proteins, lipids, and nucleic acids. This composition facilitates selective binding to target cells via interactions with overexpressed receptors such as EGFR, integrins, and folate receptors, commonly found on oral cancer cells (Nguyen Cao et al., 2021). These targeting mechanisms reduce off-target effects, significantly mitigating collateral damage from conventional chemotherapy. Exosomes possess intrinsic targeting capabilities towards OSCC cells due to specific surface proteins and lipids that interact with receptors overexpressed in oral cancer, enabling more precise drug delivery (Ma et al., 2024).

Exosomes are emerging as promising carriers for RNA-based therapies in oral cancer, particularly for delivering siRNA and miRNA. They offer a protective environment that shields RNA molecules from enzymatic degradation in the bloodstream and improves cellular uptake (Wang K. et al., 2021), enabling targeted modulation of tumor-associated genes. The delivery of miRNA mimics such as let-7 has shown potential to suppress oncogenic pathways and metastasis (Otmani and Lewalle, 2021). Despite promising results, challenges persist in optimizing RNA loading, stability, and release kinetics within exosomes to achieve consistent therapeutic outcomes. Ongoing research in RNA engineering and loading methods is essential to fully harness their potential. Exosomes offer a compelling platform for delivering siRNA and miRNA to OSCC cells, protecting RNA from degradation and enabling targeted gene silencing to suppress oncogenic pathways (Sayyed et al., 2021).

While exosomes show considerable promise, several challenges hinder their clinical implementation. A primary limitation is the difficulty in isolating and purifying exosomes at scale, as current techniques (ultracentrifugation, size-exclusion chromatography, immunoaffinity capture) yield heterogeneous populations, complicating standardization (Lee et al., 2020). Advances in isolation technologies are urgently needed to ensure homogeneity and reproducibility. Loading therapeutic agents, especially large or hydrophilic drugs, into exosomes presents another challenge; techniques like electroporation, sonication, and chemical conjugation may compromise exosome integrity and functionality (Nguyen Cao et al., 2021). Additionally, although generally considered immunologically inert, exosomes’ potential to trigger immune responses, particularly in patients with underlying immune disorders, cannot be entirely excluded. Strategies to reduce immunogenicity, such as using autologous exosomes or surface modifications, are under active investigation. Challenges in the clinical translation of exosome-based DDS for OSCC include scalable isolation, efficient drug/RNA loading, and ensuring consistent targeting and minimal immunogenicity.

Exosomes represent a transformative and versatile platform for drug delivery in oral cancer therapy, offering advantages like biocompatibility, intrinsic targeting, and the ability to deliver complex therapeutics such as RNA. These features position exosomes as superior alternatives to synthetic delivery systems. However, addressing challenges related to scalability, standardization, and cargo loading is essential for clinical translation (Nguyen Cao et al., 2021). The future of exosome-based therapies lies in integrating these natural carriers with advances in nanotechnology and molecular biology to optimize their design and functionality. Innovations such as engineered exosomes with enhanced targeting specificity, improved drug loading capacity, and real-time monitoring capabilities could significantly enhance their therapeutic potential. As interdisciplinary research continues to refine these systems, exosomes hold the promise of revolutionizing oral cancer treatment and advancing personalized medicine (Familtseva et al., 2019; Wu et al., 2024).

Intelligent hydrogels offer significant advantages in cancer treatment, particularly for localized oral cavity therapies. Their biocompatibility and biodegradability minimize adverse reactions, making them ideal for use with toxic anticancer drugs while enhancing patient tolerance, crucial for compliance and quality of life (Remiro et al., 2022).

A major benefit is their injectable liquid state and subsequent in situ gelation at the tumor site. This minimally invasive approach is especially advantageous in the sensitive oral cavity, were surgical interventions risk complications. Additionally, hydrogels provide controlled drug release, ensuring sustained therapeutic concentrations over extended periods, essential for managing chronic conditions like oral cancer requiring long-term treatment efficacy (Zhao et al., 2022).

Another key advantage is their capacity for simultaneous multi-drug delivery, enabling combination therapies with synergistic outcomes. This multidrug strategy is valuable in overcoming drug resistance by targeting multiple pathways. Studies demonstrate hydrogels’ potential in improving therapeutic indices, reducing systemic exposure, and addressing complex tumor microenvironment dynamics, positioning them as a transformative tool in localized cancer therapy (Li et al., 2016).

Thermosensitive hydrogels undergo a sol-to-gel transition with temperature changes. Injectable as a liquid at room temperature, they solidify at body temperature, forming a depot for sustained drug release (Li et al., 2016). Incorporating nanoparticles, like carboplatin, can further improve therapeutic agent sustained release, showing promise where precise drug delivery is crucial (Thakur et al., 2020).

Mucoadhesive patches offer distinct advantages as a non-invasive, localized drug delivery method, particularly in the challenging oral cavity.

Nanofiber-based DDS present several advantages for advanced oral lesions:

A notable application involves polyvinyl alcohol (PVA)-based membranes loaded with glucose oxidase (GOx), manganese dioxide (MnO₂), and rapamycin, exemplifying a multi-modal therapeutic approach:

Nanofibers are compatible with advanced therapeutic modalities like Photodynamic Therapy (PDT), which utilizes a photosensitizer activated by specific light wavelengths to generate ROS and induce cytotoxicity (Sun et al., 2022). A hybrid hydrogel system incorporating nanofibers demonstrates this synergy. The system combines mesoporous silica nanoparticles (MSNs) loaded with IR820, a cyanine dye with photothermal properties, and DOX, an established chemotherapeutic agent (Wu et al., 2021). Upon near-infrared (NIR) light irradiation, this system achieves synchronized photothermal and chemotherapeutic effects:

The integration of nanofiber-based systems with multi-drug and multi-modal approaches significantly advances the treatment of advanced oral lesions (Sun et al., 2022). By combining chemotherapy, photothermal, and starvation therapy, these systems address critical limitations like tumor heterogeneity and resistance (Ying et al., 2020).

Future research should optimize nanofiber physicochemical properties, including degradation rates, mechanical stability, and drug-release kinetics, to enhance functionality in the oral environment. Personalized formulations tailored to individual tumor biomarkers and local microenvironments could further improve therapeutic outcomes. Clinical trials are essential to validate efficacy and safety, ensuring transition from experimental models to practical applications.

Nanofiber-based systems, especially with complementary therapies, represent a versatile and effective platform for localized drug delivery in oral cancer treatment (Bishnoi et al., 2023). Their ability to achieve controlled, multi-drug release while minimizing systemic toxicity offers significant potential to improve patient outcomes through targeted and minimally invasive strategies.

Cancer cell membrane-coated nanoparticles (CCM-NPs) encapsulating photosensitizers like indocyanine green (ICG) and autophagy inhibitors such as hydroxychloroquine (HCQ) demonstrate efficient tumor targeting through homologous recognition. Poly (β-amino esters)/PLGA nanoparticles offer a stable platform for co-delivering PTT agents (e.g., ICG) and immunotherapeutic agents (e.g., HCQ) (Shi et al., 2024; Wu et al., 2024). This biomimetic approach improves cellular uptake and retention of therapeutic agents, enhancing PTT and immunotherapy efficacy. These systems also enhance drug solubility and bioavailability, enabling precise, localized delivery while minimizing systemic toxicity.

These molecules bind selectively to overexpressed receptors or antigens on cancer cells or within the TME, promoting site-specific drug accumulation (Chehelgerdi et al., 2023). RGD peptides, for instance, target integrins (e.g., αvβ3, αvβ5), commonly overexpressed in OSCC, improving delivery efficiency (Wang Z.-Q. et al., 2015; Javid et al., 2024). Ligands like hyaluronic acid targeting CD44 are also widely explored for OSCC (Pornpitchanarong et al., 2020; De Capua et al., 2021).

Nanoparticles conjugated with tumor-specific antibodies provide high selectivity for tumor-associated antigens, enhancing intracellular drug delivery and therapeutic concentration. Additionally, they can engage immune effector cells or block immune checkpoints to stimulate anti-tumor responses (Liu et al., 2021; Tian et al., 2022). EGFR-targeting antibodies, overexpressed in OSCC, are under investigation for nanoparticle-mediated delivery (Cao et al., 2022; Hasan et al., 2025).

Functionalizing nanoparticles with immunostimulatory agents such as Toll-like receptor (TLR) ligands or STING agonists promotes dendritic cell activation, antigen presentation, and cytotoxic T cell responses (Zhi et al., 2023; Chen et al., 2024). Targeted delivery to immune cells in the TME or lymph nodes can help reverse local immunosuppression and support combination therapy (SureshBabu et al., 2021; Wells et al., 2024).

These functionalization strategies are particularly valuable in combination therapies. For example, integrating PTT or PDT with ligand- or immunomodulator-functionalized nanoparticles enhances the targeted delivery of photosensitizers or photothermal agents (Li et al., 2023; Shi et al., 2024). This synergy increases local therapeutic efficacy and, when combined with immune activation, can convert immunologically “cold” tumors into “hot” ones, improving response and overcoming resistance (Wu et al., 2021; Shi et al., 2024).

Functionalizing nanoparticles with ligands, antibodies, or immunomodulators holds significant potential for improving drug targeting, immunogenicity, and treatment outcomes in oral cancer (Chen et al., 2024; Wells et al., 2024). Continued research is essential to optimize these systems for clinical translation and large-scale application in OSCC therapy.

DDS for oral cancer must meet strict regulatory standards, demonstrating biocompatibility and minimal off-target accumulation—especially important given the proximity of vital oral structures. A thorough understanding of pharmacokinetics and tissue-specific biodistribution is essential to reduce side effects and improve efficacy (Wu et al., 2024). Approval depends on validating the selective accumulation of advanced systems, such as cell membrane-functionalized nanoparticles, in tumor tissues while sparing healthy ones (Shi et al., 2024).

Scaling DDS for oral cancer is complex due to tumor heterogeneity and the need for high therapeutic specificity. Achieving consistency in particle size, drug loading, and release profiles is critical for targeted delivery and minimizing systemic toxicity (Endo et al., 2013; Goldberg et al., 2022; Peng et al., 2022; Wu et al., 2024). Adhering to Good Manufacturing Practices (GMP) adds further complexity, particularly for patient-specific formulations, posing a barrier to commercialization.

High costs associated with advanced materials and complex manufacturing processes remain a significant barrier. Although DDS show superior therapeutic potential, their cost often exceeds that of conventional therapies. Demonstrating cost-effectiveness requires comprehensive models that account for long-term savings through better efficacy and reduced adverse effects. Lowering production costs through scalable, GMP-compliant methods is essential for broader clinical adoption (Bosetti and Jones, 2019).

Tailoring DDS to the biological and molecular heterogeneity of OSCC—including HPV-related and tobacco/alcohol-associated subtypes—demands advanced diagnostics and biomarker identification (Shi et al., 2023). Targeted systems designed for specific receptors or altered pathways, such as EGFR or PD-1/PD-L1, could improve precision and efficacy (Maeda et al., 2009; Alexander-Bryant et al., 2017; Peng et al., 2022). Nanoparticles responsive to tumor microenvironmental conditions, such as acidic pH, represent a promising direction (Essawy et al., 2021; Li et al., 2022). Nonetheless, translating these personalized approaches into routine clinical practice remains a technical and economic challenge, particularly in low-resource settings.