Design and Application of Multiscale Systems and Scaffolds Based on Functional Polymeric Materials in Treating Chemoradiotherapy-Induced Oral Mucositis

Introduction

Cancer represents a significant public health challenge confronting the global community in the 21st century. As per the data provided by the National Institutes of Health in the United States, the annual incidence of cancer is projected to rise to 23.6 million by 2030. Radiotherapy (RT) and chemotherapy (CT) currently serve as the principal modalities for cancer treatment.¹ Nevertheless, owing to their non-specific cytotoxicity, these treatment modalities, while eradicating rapidly proliferating tumor cells, cause indiscriminately harm to actively regenerating normal tissues, consequently giving rise to a series of treatment - associated complications.² Among these, oral mucositis (OM) ranks as one of the most prevalent complications subsequent to radiotherapy and chemotherapy. Epidemiological data indicate that the incidence of OM is remarkably high.³ Among patients undergoing standard chemotherapy, the incidence rate ranges from approximately 20% to 40%. Among patients receiving radiotherapy or combined chemoradiotherapy, the incidence rate can exceed 80%, and approximately one-third of these patients will develop severe (grade 3–4) OM.^2,4,5 OM induces severe pain, dysphagia, xerostomia, and secondary infections, leading to a marked reduction in patients’ quality of life by impairing normal eating. Furthermore, severe OM can necessitate interruptions in radiotherapy or chemotherapy, thereby compromising overall cancer treatment outcomes.^6–8

The onset and progression of OM are highly intricate, featuring multistage and dynamic evolution. Sonis et al classified OM into five stages according to its pathological alterations: the initiation stage, the primary injury stage, the signal amplification stage, the ulceration stage, and the healing stage. i) Initiation: radiotherapy and chemotherapy induce excessive oral reactive oxygen species (ROS) production, causing DNA damage and basal cell apoptosis. ii) Primary injury: ROS triggers innate immunity, activating P53, Wnt, NF-κB pathways and upregulating TNF-α, ILs, COX-2, CAMs. JNK activation enhances Nrf2 expression, exacerbating tissue damage. iii) Signal amplification: Pro-inflammatory cytokines establish a positive feedback loop, driving cell apoptosis and bacterial invasion via loosened epithelial junctions. PAMPs further upregulate inflammation, forming a vicious cycle. iv) Ulceration: Prolonged inflammation disrupts epithelial integrity, forming ulcers that facilitate microbial invasion into connective tissues, increasing bacteremia/sepsis risk. v) Healing: Post-treatment, stabilized oxidative stress and microbial remodeling, coupled with extracellular matrix/mesenchymal signaling, mediate epithelial regeneration.^5,9 Nevertheless, the genetic makeup of the regenerated mucosal epithelium differs from the original, potentially reducing the tissue’s tolerance to radiotherapy and chemotherapy.

Currently, the management of OM primarily emphasizes preventive measures and symptomatic alleviation, including infection prevention, inflammation control, pain relief, and tissue healing promotion. Chlorhexidine mouthwash, an anti-infective agent, can reduce the incidence of OM by inhibiting the colonization of bacteria, fungi, and viruses.¹⁰ Rebamipide, an anti-inflammatory and analgesic agent, shortens the duration of OM in cancer patients undergoing radiotherapy and chemotherapy through the suppression of ROS production in inflammatory cells and the elimination of hydroxyl radicals. Periplaneta americana Extract Liquid, a therapeutic agent facilitating tissue repair, notably mitigates the severity of OM.^11–13 Nonetheless, the dynamic oral microenvironment, which is distinguished by continuous moisture, a dense microbial community, and diverse bioactive enzymes, in conjunction with the continuous mechanical stress during mastication, causes the retention time of conventional therapeutic agents to be less than 30 minutes. As a result, these agents are insufficiently retained, leading to a bioavailability of less than 20%. This situation substantially impedes the effectiveness of the prevention, treatment, and management of OM, thus making it imperative to develop more advanced strategies for its prevention and control.^14–17

With the progress of materials science, functional polymer materials have shown considerable potential in this field. Notably, numerous functional polymeric materials featuring outstanding biocompatibility can adhere tightly to mucosal tissues within the humid oral environment. This allows them to effectively withstand saliva flushing, enzymatic degradation, and mechanical stress from mastication, thus offering essential support for the long-term retention of drugs.¹⁸ In light of these characteristics, functional polymeric materials, including hydrogels, patches, and microspheres, have been continuously explored and developed. These materials are capable of achieving sustained drug release at the lesion site, effectively suppressing the infiltration of inflammatory cells, and facilitating the migration of epithelial cells. Consequently, they can optimize the oral microenvironment, rendering it more favorable for the treatment of OM.¹⁹ However, a comprehensive overview of their design and application is still absent. In this review, we systematically summarize the functional polymeric materials designed for the oral microenvironment in OM (Figure 1). Firstly, the microenvironment of OM is introduced, and the underlying reasons for its resistance to healing are explored. Subsequently, this review elaborates comprehensively expounds on the characteristics of various functional polymer materials and their action mechanisms in the treatment of OM, and simultaneously clarifies the therapeutic strategies for specific pathological stages. Ultimately, this paper deliberates on the current challenges in utilizing functional polymeric materials for OM treatment and anticipates future development trends in this field, with the aim of offering insights and inspiration for the development of next generation functional polymeric materials in this area.

Figure 1 Schematic diagram of the classification and key properties of functional polymeric materials for OM treatment.

The Oral Microenvironment of OM

The homeostasis of the oral microenvironment serves as the fundamental basis for maintaining mucosal health. It consists of an intact physical barrier, a suitable physiological milieu, a balanced microbial ecosystem, and effective immune surveillance.^20–22 Under normal physiological circumstances, the rich capillary blood supply, high efficiency epithelial regeneration rate, and minimal scar formation in the oral mucosal region endow mucosal lesions with rapid and efficient recuperative capacities. Consequently, oral mucosal lesions exhibit a faster healing rate compared to cutaneous wounds.^23,24 Nevertheless, under the continuous influence of radiotherapy and chemotherapy, the mucosal lesions induced by OM present clinical features of delayed healing and pathological repair. The formation of this characteristic can be ascribed to the synergistic actions of multiple factors, including alterations in salivary gland function, dysregulation of microbial communities, persistent inflammatory reactions, intense oxidative stress stimuli, and impaired regeneration of vascular endothelium (Figure 2).^25,26 Therefore, comprehending the unique pathological environment and challenges of OM is not only advantageous for the treatment and prognosis of OM but also holds substantial significance for the design of polymer functional materials specifically targeting OM.

Figure 2 Schematic diagram of the pathological mechanisms of the OM microenvironment. (A) Radiotherapy and chemotherapy lead to atrophy of the salivary glands, causing functional disorders and compositional changes. (B) Radiotherapy and chemotherapy disrupt the balance of the oral microbiota, leading to the proliferation of pathogenic bacteria and the formation of biofilms (C) Radiotherapy and chemotherapy cause immune dysfunction, which in turn triggers inflammatory responses, intensifying local inflammatory damage. (D) Radiotherapy and chemotherapy induce excessive production of reactive oxygen species, triggering oxidative stress and causing structural and functional damage to mucosal. (E) Radiotherapy and chemotherapy cause damage to the vascular endothelium, leading to abnormalities in vascular structure and function. (F) The moist environment and mechanical movement within the oral cavity result in a short drug retention time, reducing bioavailability and diminishing therapeutic efficacy. Blue arrows represents up-regulation, red arrows represent down-regulation, red X represent block generation, and blue curved arrows represent polarization or transformation.

Salivary Gland Dysfunction and Alteration of Saliva Composition

Saliva functions as a weak buffer with a pH ranging from 5.5 to 7 and is predominantly composed of water, electrolytes, digestive enzymes, metabolites, mucins, and antimicrobial peptides. These components are indispensable for basic physiological functions, such as oral lubrication, the initiation of digestion, mucosal cleansing, and antibacterial defense, thus playing a crucial role in maintaining the health of the oral mucosa.²⁷ Research suggests that in a normal oral micro - environment, saliva contributes to the repair of mucosal lesions by promoting fibroblast proliferation and migration, accelerating keratinocyte renewal, and facilitating the release of growth factors.^19,28,29 However, cancer patients undergoing radiotherapy and chemotherapy, such as multi-drug combination therapy involving 5-fluorouracil, cyclophosphamide, methotrexate, and epirubicin, may encounter significant atrophy of the salivary glands. This condition can give rise to clinical manifestations like xerostomia and taste disorders, which may further lead to secondary complications, including mucosal atrophy, thinning, and congestion, thereby aggravating OM symptoms in cancer patients. Moreover, it elevates the risk of dysphagia and pain during deglutition.^30–34 Therefore, functional polymeric materials intended for the treatment of OM should possess good wettability or enhance the secretory function of oral saliva.

Microbial Dysbiosis

The oral microbiota, serving as a critical biological determinant of the oral environment, comprises over 1,000 species of microorganisms, including bacteria, archaea, fungi, protozoa, and viruses. The substantial quantity of oral microorganisms collectively constitutes a highly diverse microbial community, which exerts a notable impact on oral health.³⁵ Nevertheless, radiotherapy and chemotherapy can disrupt the equilibrium of the oral microecology, thus converting the originally symbiotic microbial community into a contributing factor for OM.³⁶ Relevant research has indicated that chemotherapeutic agents (eg., 5-fluorouracil) can induce substantial alterations in the oral microbiota. As the degree of microbial dysbiosis escalates, the severity of OM increases accordingly.³⁷ Moreover, specific pathogens, such as Porphyromonas gingivalis and Candida glabrata, can directly interfere with the metabolism and proliferation of oral epithelial cells, thereby impeding the repair of oral mucosal lesions.³⁸ Furthermore, when bacteria and their secreted extracellular polymeric substances form biofilms, a localized anaerobic environment is established, facilitating the proliferation of Gram-negative bacteria and consequently inducing persistent infections. Additionally, biofilms also impede the effectiveness of drug treatments and enhance bacterial drug resistance.^39–41 More significantly, infections triggered by biofilm dysbiosis can further spread within local tissues, leading to deep - tissue infections such as cellulitis and abscesses, and may even induce systemic symptoms.⁴² Therefore, functional polymeric materials should concentrate on regulating the oral microbial flora and effectively inhibiting biofilm formation, which will provide crucial support for the prevention and treatment of OM.

Immunity and Inflammatory Response

Local immune dysfunction in the oral cavity and persistent inflammatory responses constitute the core pathological mechanisms underlying the onset of OM. Firstly, the radiotherapy and chemotherapy processes induce a decline in patients’ systemic immunoglobulin levels, resulting in immune dysfunction. This inhibits the body’s pathogen-elimination ability, heightens the oral mucosa’s susceptibility to bacterial infections, and subsequently triggers severe oral mucosal lesions, such as lichenoid lesions and polymorphous erythema.^43–46 Secondly, radiotherapy and chemotherapy can disrupt the balance of the immune microenvironment by interfering with the polarisation of macrophages. Specifically, they promote the long-term dominance of pro-inflammatory M1 macrophages, which stimulate inflammation and delay tissue repair by releasing TNF-α, IL-1β and other substances. Meanwhile, chemoradiotherapy inhibits the polarisation of anti-inflammatory M2 macrophages. Under normal physiological conditions, M2 macrophages can suppress the inflammatory cascade by secreting anti-inflammatory factors such as IL-10 and TGF-β. They also promote the activation of fibroblasts, angiogenesis and the migration and proliferation of epithelial cells, thereby accelerating wound healing. When the polarization of M2 macrophages is inhibited, the aforementioned tissue repair process is interrupted and anti-inflammatory and pro-regenerative signals are weakened. This delays the tissue repair process and ultimately hinders the healing of oral mucosal injuries.^47,48 In brief, radiotherapy and chemotherapy establish a unique “high-inflammation, low-defense” immune microenvironment in the oral cavity of cancer patients. Therefore, the core characteristics of functional materials for treating OM should include excellent anti-inflammatory and immune-regulatory capabilities.

Oxidative Stress and Vascular Endothelial Injury

Upon stimulation by radiotherapy or chemotherapy, mucosal tissue not only releases a substantial quantity of inflammatory factors but also initiates severe oxidative stress responses. This results in the rapid destruction of epithelial tissue, gives rise to vascular lesions, and hinders the formation of new blood vessels. Vascular endothelial cells (VECs), which constitute the structural foundation of the oral mucosal microvascular system, play a pivotal role in maintaining tissue nutrient delivery, immune regulation, and microenvironmental homeostasis.⁴⁹ During the pathological progression of OM, VECs emerge as an early and critical target of injury. Radiation and cytotoxic drugs directly inflict damage on the DNA of vascular endothelial cells and induce their apoptosis. Concurrently, radiotherapy and chemotherapy activate pro-inflammatory pathways, leading to the overexpression of cytokines such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). This causes the disruption of the vascular barrier, the initiation of microthrombosis, and ultimately leads to impairment of the mucosal microcirculation.^50,51 More gravely, pathogenic microorganisms can invade the peripheral circulation via the damaged vasculature, resulting in bacteremia and endotoxemia.⁵² At this juncture, the mucosal tissue, afflicted by ischemia, hypoxia, and the accumulation of metabolic waste products, creates a harsh microenvironment that is challenging to self-repair.^53,54 Therefore, the design of functional polymeric materials capable of targeted protection of VECs, modulation of pro-angiogenic factors, and amelioration of the oxidative stress microenvironment has become a crucial direction in OM treatment.

Dynamically Hydrated Oral Microenvironment

In comparison to other tissues like the skin, the oral cavity sustains a consistently humid microenvironment and endures mechanical stress during mastication. These features substantially restrict the bioavailability of oral medications, thus imposing rigorous demands on the functional polymeric materials utilized in the treatment of oral diseases.⁵⁵ The continuous secretion of endogenous saliva, along with the exogenous moisture introduced by food and beverages, is the primary contributor to the humidity of the oral microenvironment. The combined influence of these factors can disrupt the cross-linked network of materials, impeding their adhesion to the tissue surface.⁵⁶ Moreover, the movements related to mastication, speech, and swallowing, driven by the oral cavity and the adjacent maxillofacial regions, frequently lead to deformation and detachment of these materials due to their inadequate mechanical strength. As a result, it is difficult for them to adhere to the mucosal surface for a sufficient period.^16,57,58

An ideal oral functional polymeric material should display strong wet adhesion and outstanding mechanical strength, enabling it to resist the effects of saliva flow and oral mucosal movement. However, it is crucial to note that an excessively high level of adhesion and mechanical strength in functional polymeric materials does not necessarily confer benefits. Materials with high viscosity and strength often face challenges in degradation within the oral cavity, and a pronounced foreign body sensation may disrupt daily physiological activities such as eating, ultimately reducing patient compliance with these materials.¹⁹ Additionally, high strength materials can cause mucosal abrasion due to mechanical incompatibility with the surrounding tissues, potentially resulting in secondary damage.⁵⁹ Therefore, functional polymeric materials used in oral medical treatment must possess adhesion and mechanical strength that are suitable for the oral microenvironment.

Micro-Nano Hydrogels for OM Treatment

Due to their distinctive physicochemical properties, hydrogel materials exhibit considerable potential in the treatment of OM.⁶⁰ Firstly, as three-dimensional hydrophilic networks with a water content generally surpassing 90%, hydrogels can simulate the moist microenvironment of the native extracellular matrix (ECM). This offers continuous hydration and a physical barrier to the wound area, while facilitating cell proliferation, migration, and tissue facilitating cell proliferation, migration, and tissue regenerationregeneration.^61,62 Secondly, hydrogels possess outstanding biocompatibility and controllable drug release characteristics, allowing for the accurate delivery of bioactive molecules, including antimicrobial agents, anti-inflammatory drugs, or growth factors, to the inflammatory site. This significantly elevates local drug concentrations and diminishes systemic adverse effects.⁶³ This precise and sustained local therapeutic approach presents notable advantages in ameliorating the OM microenvironment and enhancing the efficacy of tumor treatment. Noteworthy, hydrogel materials demonstrate extensive applicability throughout the five pathological stages of OM as posited by Sonis et al Capable of establishing a physical barrier in vivo and facilitating controlled drug release, they are especially significant for the signal amplification stage (for modulating inflammation) and the ulceration stage (for protecting wound surfaces and promoting healing).

In recent years, hydrogel design has increasingly gravitated towards functionalization and intelligence, resulting in the development of diverse functional polymeric hydrogel systems specifically tailored for OM treatment.^64,65 Among these functional hydrogels, in situ hydrogels have attracted substantial attention because of their unique injectability and environmentally responsive gelation properties. Once applied to the lesion site, its liquid precursor can swiftly transform into an adhesive three-dimensional network structure in response to environmental stimuli such as temperature, pH, light, or ultrasound. This “sol-to-gel” transition feature enables it to precisely adapt to irregular mucosal surfaces, achieving prolonged retention and thus providing an excellent platform for the controlled and sustained release of drugs.^18,66–68 The subsequent section will concentrate on discussing the most representative functional polymeric hydrogels therein.

To meet the therapeutic requirements of the intricate pathological processes of OM, functional hydrogels present multi-level intervention strategies. Firstly, in the context of fundamental antimicrobial and physical barrier functions, the chitosan-gelatin in situ hydrogel developed by the V. Tamara Perchyonok et al can establish a long-lasting protective layer on the mucosal surface owing to its outstanding bioadhesiveness. Moreover, it offers sustained antimicrobial activity through the controlled release of nystatin.⁶⁹ Secondly, with respect to pain management, a crucial aspect of OM treatment, the poloxame-based spray gel developed by Li et al promptly form a film on the mucosal surface, achieving long term analgesia (Figure 3A).⁷⁰ In subsequent investigations, the incorporation of sodium lauryl sulfate as a solubilizer notably enhanced the drug loading capacity for poorly soluble analgesic agents, prolonging therapeutic effects while mitigating side effects.⁷¹ Furthermore, Zhang Y et al incorporated the active components of the oral care solution into a hydrogel. By leveraging its sustained release characteristics, this formulation continuously inhibits the NF-κB signaling pathway, thereby intervening in the inflammatory progression of OM, facilitating mucosal repair, and alleviating pain.⁷²

Figure 3 (A) Mucoadhesive in situ forming gel containing a novel drug molecule, Bupivacaine γ-Linoleate, for oral mucositis pain control. Reproduced with permission from Ref.70 Copyright 2020, Elsevier. (B) Schematic of Col/HA-E/Alg Hydrogel Structure and Treatment Mechanism for Chemotherapy-Induced Oral Mucositis (CIOM). Reproduced with permission from Ref.73 Copyright 2025, American Chemical Society. Blue curved arrow represents macrophages polarized toward M2 and The blue straight arrow represents down-regulation.

Furthermore, the design of in situ hydrogels is progressing towards multifunctional integration and self-driven therapy. For instance, a multicomponent hydrogel founded on human recombinant collagen III not only demonstrates outstanding wet tissue adhesion but also simultaneously exerts antioxidant, anti-inflammatory, and immunomodulatory functions. Through the promotion of angiogenesis and collagen deposition, it comprehensively enhances the wound healing microenvironment of OM (Figure 3B).⁷³ Additionally, Pan et al fabricated a semi-interpenetrating network hydrogel that co-loads oridonin and DNase I, which notably expedites the repair of OM lesions while synergistically offering antimicrobial and anti-inflammatory effects.⁷⁴

It is worthy of note that advanced hydrogel systems also present advantages in synergistic therapy and precise regulation of drug release. The guanosine-polyvinyl alcohol (G-PVA) hydrogel developed by Ding et al shows remarkable performance in this aspect. This system is constructed through a one pot synthesis method to form a supramolecular structure, which provides a strong wet adhesion of 74.16 kPa for stable retention in the oral cavity, thus laying a foundation for precise local delivery. Furthermore, this hydrogel can significantly alleviate radiation-induced oxidative stress and DNA damage, reducing the lesion area by 52.23% in an animal model. This underscores its synergistic therapeutic effects in mucosal protection and oxidative regulation, presenting a promising new clinical strategy for preventing OM (Figure 4A).⁶⁵

Figure 4 (A) Schematic Illustration of G-PVA hydrogel for efficient treatment of radiation-induced oral mucositis. Reproduced with permission from Ref.65 Copyright 2025, Royal Society of Chemistry. (B) Schematic Illustration of Action of KPV@PPP In Situ Mucoadhesive Hydrogel in Treating Chemotherapy-Induced Oral Mucositis. Reproduced with permission from Ref.18 Copyright 2022, Royal Society of Chemistry. (C) Schematic Illustration PHB hydrogel for efficient treatment of CIOM. Reproduced with permission from Ref.75 Copyright 2025, Elsevier.

In the terms of inflammation regulation, Shao et al engineered an in situ mucoadhesive hydrogel encapsulating the tripeptide KPV. Through the inhibition of pro-inflammatory cytokines IL-1β and TNF-α, the up-regulation of the anti-inflammatory cytokine IL-10, and the facilitation of epithelial proliferation and differentiation (manifested as the up-regulation of CK10 and PCNA expression), this hydrogel concurrently attains anti-inflammatory, antibacterial, and tissue repair efficacy (Figure 4B).¹⁸

Additionally, Wu et al constructed a hyaluronic acid-based composite hydrogel (PHB). By embedding core-shell microgels to encapsulate the growth factor (core) and lidocaine (shell), this hydrogel facilitates temporally regulated drug release. This hydrogel demonstrates outstanding mucosal adhesion (with a displacement of merely 5.5 mm within 24 hours), remarkable antibacterial characteristics, and sustained drug release over a 24 hour period, synergistically promoting analgesia, tissue regeneration, and expediting the healing of otitis media (Figure 4C).⁷⁵

The temperature-responsive hydrogels, which experience reversible sol-gel phase transitions, present significant potential for localized drug delivery within the oral cavity. Thermosensitive materials, including Poloxamer and Poly (N-isopropylacrylamide) (PNIPAAm), display a phenomenon wherein the polymer molecular chains are highly hydrated via hydrogen bonding when the temperature is below the lower critical solution temperature (LCST). At this stage, the system exists in a flowing sol state. As the temperature surpasses the LCST, thermal energy disrupts the interaction between the polymer and water, and the hydrophobic segments prevail in intermolecular cross-linking, consequently forming a three-dimensional gel network (Figure 5A).^76–78 The primary advantage of this type of thermosensitive gel resides in its superior clinical applicability and retention capacity at the lesion site. The precursor solution can comprehensively cover irregular wounds. Triggered by body temperature, it rapidly gels and adheres to the mucosal surface, effectively resisting saliva erosion and mechanical perturbations. This offers an ideal platform for long-term drug sustained release and notably enhances drug delivery efficiency and patient compliance.⁷⁹ This is clearly manifested in the gelation and adhesion process of the PolyLA - SQBA hydrogel (Figure 5B).⁸⁰ For example, Bakhshi et al developed a thermosensitive adhesive hydrogel based on trimethyl chitosan derivatives, which was capable of achieving sustained drug release and mucosal retention in animal models, effectively promoting the healing and epithelial regeneration of OM (Figure 5C).^81,82

Figure 5 (A) Drug release from thermoresponsive polymeric micelles upon temperature increase. Reproduced with permission from Ref.78 Copyright 2015, Elsevier. (B) Schematic illustration of the preparation, characteristics, and applications of PolyLA-SQBA thermoresponsive hydrogel. Reproduced with permission from Ref.80 Copyright 2025, Elsevier. (C) Schematic diagram of a thermoresponsive multifunctional hydrogel based on Cur-VE-Zn complex for the treatment of oral mucositis. Reproduced with permission from Ref.82 Copyright 2025, Elsevier. Blue down arrow represents down-regulation and red up arrow represents up-regulation.

The pH-responsive hydrogel, endowed with the capabilities of environmental sensing and intelligent feedback, exhibits distinctive advantages in the local targeted therapy of OM. Its mechanism of action originates from the alterations in the ionization states of ionizable groups (eg., carboxyl groups, amino groups, etc.) within the polymer network under diverse pH environments, which subsequently result in phase behavior transitions, such as swelling, contraction, or degradation, of the gel network structure (Figure 6A).^76,83 Under the pathological conditions of oral mucositis, inflammatory tissues generate a substantial amount of lactic acid through metabolic activities, establishing a weakly acidic microenvironment (pH 5.5–6.5), which is notably lower than the neutral pH condition of healthy oral mucosa. This disparity provides a crucial basis for pH-responsive hydrogels to achieve targeted drug delivery to inflammatory sites. Consequently, pH-sensitive polymers, such as chitosan, sodium alginate, and their derivatives (eg., methacrylated sodium alginate), as well as polyacrylic acids (eg., carbomer), are extensively utilized to construct therapeutic carriers for the treatment of OM.⁸⁴

Figure 6 (A) Chemical structural changes of pH-responsive functional groups. Reproduced with permission from Ref.83 Copyright 2015, Elsevier. (B) Schematic illustration of a pH-responsive composite hydrogel based on SA/CMCS for multi-mechanistic therapy of wound infection and skin regeneration. Reproduced with permission from Ref.85 Copyright 2025, Elsevier.

Galbis et al demonstrated that by modulating the composition of the dispersion system of chitosan-based hydrogels, the swelling behavior, rheological strength, and drug release kinetics of the hydrogels can be precisely regulated, thereby attaining adaptive responses to the microenvironment of the lesion site and long-term drug control.⁸⁶ The pH-responsive delivery system developed by Li et al can initiate the release of antibacterial agents and immunomodulators in the weakly alkaline environment of periodontal pockets. By targeting multiple points to intervene in the “infection-inflammation-bone destruction” vicious cycle, it offers a novel approach for the combined treatment of periodontal-related diseases.⁸⁷ The SCSC hydrogel constructed with sodium alginate and carboxymethyl chitosan, through the “sensing-response-treatment” mode, not only enhances the retention and efficacy of the drug in the lesion area but also significantly improves the accuracy and safety of the treatment (Figure 6B).⁸⁵

In comparison with endogenous stimulus-responsive hydrogels, light-responsive and sonoresponsive hydrogels, characterized by their non-invasive nature, remote controllability, and superior spatiotemporal resolution, have demonstrated significant potential in the treatment of oral cavity diseases. The oral cavity is a cavity that allows for direct observation and facile operation. The core mechanism involves the conversion of external physical stimuli (light or sound) into chemical or physical signals, which subsequently precisely regulate the drug release behavior or structural alterations of the gel system, facilitating remote “on-demand” control of the treatment process.^88,89 Photo-responsive hydrogels are typically functionalized by incorporating photo-sensitive groups (eg., azobenzene, spiropyran, etc.) into the polymer network. Under specific wavelengths of light, these groups can undergo reversible isomerization, dimerization, or cleavage reactions, leading to changes in the conformation, hydrophobicity, or crosslinking degree of the polymer network, thereby enabling the on demand controlled release of drugs.^89,90 The molecular structure and light response mechanism of the photosensitive groups upon which the photosensitive hydrogel relies are presented in Figure 7A.

Figure 7 (A) Molecular structures of typical photosensitive groups used for constructing light-responsive hydrogel systems. Reproduced with permission from Ref.88 Copyright 2011, Elsevier. (B) Schematic diagram of DCS-RuB2A2 light-responsive antibacterial hydrogel promoting oral mucosal repair. Reproduced with permission from Ref.91 Copyright 2022, KeAi Communications Co. Ltd. (C) Schematic illustration of the near-infrared (NIR) photothermal-responsive mechanism of a NIR-responsive nanocomposite hydrogel based on metal nanoparticles. Reproduced with permission from Ref.92 Copyright 2021, American Chemical Society. (D) Working mechanism and in vitro drug release results of an ultrasound-responsive drug-loaded hydrogel. Reproduced with permission from Ref.93 Copyright 2024, Elsevier. ** represent p < 0.01.

Professor Zhao et al developed a light-responsive antibacterial chitosan hydrogel named DCS-RuB2A2. In the dark, it can provide a physical barrier for oral mucosal wounds and support the growth of mesenchymal stem cells. When exposed to visible light, it can activate the antibacterial function and achieve the repair of oral mucosal defects (Figure 7B).⁹¹ Shen et al⁹² designed a near-infrared light-responsive nanocomposite hydrogel loaded with gold nanoparticles and chemotherapy drugs. This hydrogel can utilize the photothermal effect of the gold nanoparticles to induce local heating under near-infrared laser irradiation. This not only triggers the explosive release of the drugs but also synergizes with the photothermal therapeutic effect, enhancing the killing effect on deep tumors (Figure 7C).⁹² Acoustic responsive hydrogels (commonly referred to as ultrasonic responsive) primarily trigger their responses through the mechanical effects, cavitation effects, or thermal effects generated by ultrasonic irradiation.⁸⁹ For example, the reversible host-guest cross-linked hydrogel designed by Fabiilli et al exhibits reversible dissociation and reformation of its cross-linked network upon low-intensity pulsed ultrasound irradiation. This not only enables on-demand drug release but also makes multiple, pulsed drug administration feasible due to its self-healing property (Figure 7D).^93–95

Nevertheless, despite the substantial potential demonstrated by light-responsive and sono-responsive systems, these systems continue to encounter a series of translational obstacles. Firstly, the posterior buccal, pharyngeal, and retrolingual regions within the oral cavity are deeply situated and spatially restricted, characterized by intricate anatomical structures. These features impose constraints on direct visualization and manipulation. This phenomenon is especially pronounced in patients with radiation-induced trismus, where the severely limited jaw opening significantly hampers the placement of instruments and the precise targeting of light/ultrasound beams. Secondly, the dynamically hydrated microenvironment and pathological tissue characteristics of oral mucositis (including edema, ulceration, and vascular hyperpermeability) further compromise the efficacy of stimulus signals. Ultimately, current clinical light/NIR and ultrasound devices for localized stimulation are mainly designed for readily accessible sites such as the skin or anterior oral mucosa, and are deficient in miniaturized, flexible, and sterile operable probes appropriate for the deep oral cavity. Consequently, for patients presenting with concurrent severe trismus and mucosal hypersensitivity, the direct utilization of ultrasound/laser probes for detecting deep-seated lesions in posterior buccal and pharyngeal regions is not currently clinically viable for routine application.^96,97

To address the continuous mechanical stress and the “high-inflammation, low-defense” immune dysregulation in the oral environment of OM, multifunctional hydrogels with self-healing properties have emerged as a cutting-edge research direction. Such hydrogels can resist structural damage caused by shear forces while effectively regulating immune responses. For instance, Yu et al developed a multifunctional self-healing hydrogel based on chitosan, whose dynamic imine bond and hydrogen bond networks endow the material with excellent self-healing capabilities. This enables it to rapidly repair structural damage induced by mechanical stress, maintaining long-term mucosal adhesion and stable drug release. More importantly, the hydrogel can effectively modulate the polarization of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby creating an immune microenvironment conducive to repair at the wound site.⁹⁸

Micro-Nano Patch for OM Treatment

Oral mucosal patches function as a localized drug delivery system, which facilitates targeted drug delivery and sustained release through their bilayer structure, exhibiting substantial advantages in the treatment of OM.^39,99 The outer layer acts as a barrier against external stimuli, while the inner layer directly administers drugs to the lesion site.^100,101 This bilayer configuration not only enhances the adhesive stability of the patch in moist environments but also ensures extended retention within the dynamic oral cavity, thus maintaining stable drug concentrations and promoting the healing of OM.^102,103 When integrated with microneedle array technology, innovative patch designs enable deep drug delivery, effectively alleviating mucosal inflammation and promoting tissue repair.^104,105 Functional polymeric patches, tailored to specific clinical requirements across diverse treatment scenarios, present a wide array of application prospects, demonstrating a trend towards precision, personalization, and minimally invasive approaches in clinical research. In addition, the robust adhesiveness and sustained drug release characteristics of patches render them highly suitable for the treatment of the ulceration stage, which is the core phase necessitating long-term analgesic and anti-inflammatory effects. Moreover, they can intervene in the signal amplification stage (for early-stage intervention) and the healing stage (to offer a protective microenvironment).

Maheen et al developed a bilayer mucoadhesive patch based on poly (methyl methacrylate- co-methyl methacrylate) and gelatin. The gelatin layer provides long term mucosal adhesion, and the methacrylic acid layer enables programmed controlled drug release. This design allows for the co-loading of ropivacaine and itopride, synergistically managing both the local pain associated with OM and systemic nausea and vomiting symptoms.¹⁰³ Li et al incorporated zinc tannate nanoparticles into tannic acid modified polyvinyl alcohol to fabricate a patch with strong wet adhesion. This patch sustainably releases zinc ions and enhances mucosal repair by activating the KLF5/FoxO signaling pathway, offering an innovative solution for wound healing in OM (Figure 8A).¹⁰⁴ Similarly, Elhabal et al developed a dual function nanoemulsified mucoadhesive buccal film loaded with curcumin and lidocaine. This film enables efficient localized drug release and provides combined anti-inflammatory, analgesic, and mucosal healing effects. By inhibiting the MMP-9 and NF-κB pathways, it accelerates wound healing, presenting an effective approach for treating OM (Figure 8B).¹⁰⁶

Figure 8 (A) Fabrication of PT@Zn hydrogel and its therapeutic mechanism for radiation-induced oral mucositis via zinc homeostasis regulation and KLF5 activation. Reproduced with permission from Ref.104 Copyright 2025, Elsevier. (A1) Following cellular phagocytosis, the zinc tannate nanoparticle release zinc ions, consequently restoring zinc homeostasis; (A2) Zinc supplementation activates the KLF5/FoxO signaling pathway in mucosal epithelial fibroblasts to enhance cellular activity; (A3) Upon activation, mucosal epithelial fibroblasts facilitate collagen secretion and extracellular matrix formation. (B) Fabrication, characterization, and in vivo assessment of curcumin-lidocaine dual-action nanoemulsified mucoadhesive buccal films for non-invasive oral mucositis therapy targeting MMP-9 and NF-κB pathways. Reproduced with permission from Ref.106 Copyright 2025, Taylor & Francis Group. (C) Schematic illustration of the functional hydrogel system based on EGCG-Eu3+ coordination for anti-inflammatory, antibacterial, and angiogenic therapy. Reproduced with permission from Ref.107 Copyright 2025, Elsevier. (D) Schematic diagram of Apr@PMPB@S buccal tablet for anti-inflammatory and wound-healing on chemotherapy-induced oral mucositis. Reprinted from Ref.108 Wiley.

Within the field of biomimetics, biologically inspired patch designs have substantially improved wet adhesion and stability. For instance, Ryu et al devised a mussel inspired polysaccharide oral patch termed “Chitoral”. Upon coming into contact with saliva, it promptly forms an insoluble adhesive layer, which subsequently transforms into a persistently adherent hydrogel, offering a long standing local milieu for drug retention.¹⁰⁹ Wang et al established a polyphenol coacervate derived bioadhesive glue founded on the dynamic covalent bonding between EGCG and PEG, emulating mussel inspired wet adhesion. This system attains sustained and controlled release of anti-inflammatory polyphenols, demonstrating synergistic biological effects in suppressing inflammation, preventing infection, and facilitating tissue repair (Figure 8C).¹⁰⁷

Additionally, responsive patches facilitate cascade, sustained, and comprehensive drug release, effectively suppressing OM. For example, Zhang et al, conducted a salivary amylase-responsive buccal tablet was developed. It initiates the enzyme mediated release of the anti-inflammatory drug apremilast and integrates it with the ROS scavenging ability of porous manganese-substituted Prussian blue nanocubes, thus alleviating inflammation and promoting tissue repair. This system notably improves drug retention and efficacy at the oral lesion site, presenting a novel therapeutic approach for OM (Figure 8D).¹⁰⁸

Microneedle patches, as a novel transdermal drug delivery system, offer a minimally invasive and highly efficient approach for the treatment of oral mucosal diseases.¹¹⁰ Microneedles are capable of penetrating the mucosal physical barrier in a minimally invasive fashion. Among these, dissolvable microneedles (DMNs) dissolve rapidly in tissue fluid, facilitating targeted drug delivery and precise drug release.¹¹¹ Xiao et al developed a novel detachable and dissolvable microneedle patch (DC@MNs). This patch employs ceria nanozymes loaded at the needle tips to scavenge ROS while modulating the ferroptosis pathway. It effectively penetrates the mucosal barrier, enabling targeted therapy to synergistically mitigate oxidative damage and iron overload, thereby presenting an innovative localized treatment strategy for the prevention and treatment of OM.¹¹²

Subsequently, Tang et al designed a core–shell structured dual functional microneedle patch. The outer shell enables the rapid release of lidocaine to achieve immediate analgesia, whereas the inner core facilitates the sustained release of dexamethasone to exert long term anti-inflammatory and pro-healing effects. Through a spatiotemporal controlled-release strategy, synergistic therapy is accomplished (Figure 9A).¹¹³ Similarly, Chen et al constructed a multifunctional microneedle patch based on methacrylated carboxymethyl chitosan. This patch offers rapid analgesia via the release of local anesthetics and provides antibacterial protection. The co-loaded exosomes and folic acid-modified magnetic nanoparticles synergistically modulate immunity, promote angiogenesis and epithelial repair, thus effectively accelerating the healing of oral mucositis wounds (Figure 9B).¹¹⁴ Moreover, Qu et al employed mesoporous polydopamine nanoparticles (MPDA) for drug loading and dissolvable microneedle technology to prepare a composite microneedle patch (TA@MPDA-HA/BSP MNs). This patch rapidly dissolves and efficiently delivers drugs, significantly promoting oral wound healing in a rat model at a dosage merely 10% of that of conventional formulations, presenting an efficient, low dose strategy for the local treatment of oral mucositis (Figure 9C).¹¹⁵

Figure 9 (A) Schematic Illustration of the Mechanism of Core–Shell Structured Hydrogel Microspheres (GelMA/HA) Loaded with Dexamethasone and Lidocaine in Treating Oral Ulcers. Reproduced with permission from Ref.113 Copyright 2024, Elsevier. (B) A multifunctional microneedle patch to ensure mucosal penetration for sustained delivery of therapeutic exosomes and magnetic nanoparticles that synergistically promotes oral mucosal regeneration. Reproduced with permission from Ref.114 Copyright 2024, Elsevier. Black down arrows represent down-regulation and black up arrows represent up-regulation, and red bending, red down, and red to the right arrows all represent inducing effects. (C) Schematic illustrations of the preparation of TA@MPDA-HA/BSP MN patch and its application in oral inflammatory disease. Reprinted from Ref.115 Copyright 2023, Frontiers.

In response to the requirement for deep mucosal drug delivery, Xian et al devised a silk fibroin/tannic acid-based bilayer microneedle patch. This patch integrates robust wet adhesion with a drug sustained-release capacity that endures for up to 7 days, thereby attaining painless deep targeted delivery across the mucosa.¹¹⁰ Li et al developed a transmucosal delivery system comprising a transparent collagen-polyvinylpyrrolidone (PVP) composite microneedle array integrated with a pH-responsive, double-layer functionalized backing. Leveraging the intrinsic mucosal adhesiveness of hyaluronic acid (HA), the system achieves robust mucoadhesion. PVP imparts optimal mechanical strength to enhance microneedle penetration efficacy; and the dual-layer backing enables precise, pH-triggered drug release. These features collectively improve both the efficiency of transmucosal delivery and the temporal consistency of release kinetics. This hierarchical structural design represents a novel strategy for advancing deep mucosal drug delivery platforms.¹¹⁶

Notably, the clinical application of microneedle patches should be distinguished according to the severity of OM. For Grade 1–2 OM or prophylactic purposes, microneedles can be directly applied to relatively intact mucosa to accomplish non-invasive or minimally invasive drug delivery. Conversely, in the case of Grade 3–4 OM, there are exposed ulcers lacking epithelial protection and with exposed nerve endings. Direct application of microneedles may exacerbate pain and tissue damage.

Targeting secondary infections often associated with OM, patches also demonstrate precise preventive and therapeutic effects. For example, Funahara et al developed a miconazole oral patch. Through the localized, sustained, and controlled release of antifungal drugs, it effectively inhibits Candida albicans biofilm formation, providing a critical clinical approach for preventing and treating secondary fungal infections in OM.¹¹⁷

In a word, patches assume a crucial role in analgesia, anti-inflammation, and tissue repair for OM owing to their stable protective barrier, controllable drug release characteristics, and favorable patient tolerance and compliance. As an efficient and non-invasive localized delivery platform, patches have emerged as an indispensable instrument in the clinical management of OM.^103,118,119

Micro-Nano Drug Delivery Systems for OM Treatment

Micron-based DDSs, with particle sizes ranging from 1 to 1000 μm, predominantly exist in the forms of microspheres, which are characterized by a hollow structure, and microcapsules, which feature a core-shell structure. These micron-based systems are deliberately designed with a specific particle size to accurately meet the requirements for mucosal surface retention.¹²⁰ Although micron-based DDSs encounter difficulties in penetrating biological barriers, they exhibit strong mucosal adhesiveness, allowing them to withstand saliva erosion and achieve long-term, sustained drug release. This characteristic renders them ideal carriers for chronic oral lesions and clinical situations that demand long-term maintenance treatment. For instance, Ana Sofia Ferreira and Filipa Teixeira significantly enhanced the stability of active ingredients and realized controlled release by encapsulating extracts of actinidia arguta leaves and chestnut shells within microparticles.^121,122 Additionally, Jiang et al fabricated microcarriers using chitosan. The mucosal adhesion properties and drug release regulatory capabilities of these microcarriers effectively prolonged the drug retention time and notably improved the therapeutic efficacy.¹²³

Nano-based DDSs are characterized as nanostructures with at least one dimension ranging from 1 to 100 nm. In contrast to micron-based DDSs, which demonstrate mucosal surface retention properties, nanoscale DDSs, owing to their scale-dependent functional attributes and high specific surface area, promote the penetration of biological barriers and strengthen interactions with target cells.¹²⁴ Moreover, through the precise modulation of both scale and physicochemical properties, nano-based DDSs can realize targeted drug delivery, regulate the release rate, and mitigate systemic adverse reactions.^125–127 Presently, this class of materials constitutes a crucial research emphasis in the field of OM.¹²⁸ Common nanomedicine delivery systems mainly include subtypes such as nanoparticles (NPs), nanomicelles, and nanofibers. Each subtype exhibits distinct structural and functional features, collectively constituting the core framework of nanomedicine delivery.

Among diverse types of nanomaterials, NPs present substantial advantages in augmenting drug delivery efficiency, enhancing drug delivery efficacy, and elevating binding affinity with epithelial cells, attributed to their high specific surface area and distinctive structural features.¹²⁹ Encapsulating drugs within NPs effectively enhances drug stability and solubility while modulating release characteristics to attain targeted delivery. Vilar et al utilized polyvinylpyrrolidone (PVP) to cap and modify gold NPs (10 nm), leading to the preparation of PVP-capped AuNPs, and explored their effects on experimental OM induced by 5-fluorouracil (Figure 10A).¹³⁰ Research has demonstrated that PVP-capped AuNPs achieved a significant reduction of CT-induced OM severity in hamsters through inhibition of innate immune inflammatory factors including NF-κB, TNF-α, IL-1β, COX-2, TGF-β, and SMAD 2/3 (Figure 10B).^130,131 Furthermore, PVP-AuNPs can diminish the expression of Kelch-like ECH-associated protein 1 (KEAP1), promote the upregulation of nuclear factor erythroid-2-related factor-2 (Nrf2), and consequently result in an increase in antioxidant enzymes (GSH, HO-1, and NADPH), thereby demonstrating their potential to scavenge ROS and provide protective effects against OM (Figure 10C).^130,131 Additionally, Khan et al discovered that AuNPs (6 nm) synthesized from the leaf extract of Clerodendrum inerme demonstrated remarkable antibacterial and biofilm inhibitory characteristics (Figure 10D).^131,132 Takeuchi et al administered rebamipide via chitosan-coated polylactic-co-glycolic acid (PLGA) NPs. This approach significantly enhanced mucosal adhesion and sustained-release properties, resulting in a marked reduction in the area of oral lesions in mice and facilitating the healing process.¹³³ Ribeiro et al treated a hamster model of OM with dexamethasone-loaded PLGA NPs. This strategy effectively suppressed the expression of inflammatory factors such as IL-1β and TNF-α, maintained the integrity of the mucosal structure, and concurrently reduced the dosage and systemic toxicity. It demonstrated the dual benefits of precise treatment and reduced toxicity while enhancing therapeutic efficacy.¹³⁴

Figure 10 (A) Mode of action of gold nanoparticles (AuNps) in alleviating 5-fluorouracil (5-FU)-induced oral mucositis in hamsters. Reproduced with permission from Ref.130 Copyright 2020, MDPI. (B) AuNPs block/inhibit nuclear translocation of NF-κB by reacting with IKK kinase inhibiting the downstream inflammatory response. (C) Cytoprotective response of AuNPs against ROS through the KEAP1-NRF2 pathway. (D) Proposed antimicrobial mechanisms of AuNPs. Reproduced with permission from Ref.131 Copyright 2024, Springer Nature.

Nanomicelles are nano-based DDSs formed via the self-assembly of amphiphilic polymers in aqueous solutions. Their hydrophobic cores enable the efficient encapsulation of lipophilic drugs, whereas their hydrophilic shells endow them with remarkable water solubility, biocompatibility, and mucosal retention capabilities. This structural configuration effectively surmounts the clinical challenges related to liposoluble drug delivery by augmenting drug stability and enhancing targeted delivery efficiency. For instance, Liu et al encapsulated the anti-inflammatory drug cannabidiol within fucoidan nanomicelles, leading to the accumulation and sustained release of the drug at the inflammatory site. This, in turn, reduced the area of oral lesions in mice and inhibited the infiltration of inflammatory cells (Figure 11A).¹³⁵ Analogously, Delavarianto et al utilized curcumin micelles for the treatment of OM. This treatment strategy effectively postponed the onset of symptoms and alleviated the severity of lesions by improving the bioavailability and anti-inflammatory activity of curcumin.¹³⁶

Figure 11 (A) Preparation of cannabidiol/fucoidan–deoxycholic acid nanomicelles and their delivery to inflamed tongue tissue. Reproduced with permission from Ref.135 Copyright 2022, Taylor & Francis Group. (B) Preparing the chitosan-coated Eudragit L100/human growth hormone nanofibrous sheet (CEL/hGH NS) for controlling the release of hGH. (C) Treatment of an ulcer with the CEL/hGH NS after inducing the ulcer on the oral mucous membrane by 50% acetic acid.Reproduced with permission from Ref.137 Copyright 2015, Wiley.

Nanofibers, as one-dimensional fibrous materials with nanoscale diameters, can adhere closely to diseased mucous membranes, thus enabling continuous and precise drug delivery. For example, Choi et al developed poly(methyl methacrylate-co-methyl methacrylate)/chitosan composite nanofibers loaded with human growth hormone (hGH). These nanofibers facilitated the sustained release regulation of the drug and significantly promoted the complete regeneration of oral lesion tissues in dogs (Figure 11B and C).¹³⁷ Similarly, the glutamine supported sodium alginate/polyethylene oxide (PEO) nanofibers designed by Tort et al possess excellent mucosal adhesion properties and controllable release behavior. Consequently, they provide an efficient local drug delivery platform for oral mucosal applications and demonstrate the potential of nanofibers in the treatment of OM.¹³⁸

In brief, the micron-based DDSs, characterized by their excellent mucosal retention capabilities, maintain the effective concentration at the lesion surface via continuous drug release, which is conducive to long-acting treatment. In contrast, nano-based DDSs, capitalizing on their capacity to penetrate biological barriers and their precise targeting features, can efficiently deliver drugs to the deeper layers of mucous membranes, thus expediting the wound healing process. Besides, micro-nano drug delivery systems exert their effects throughout the process from the primary injury stage to the healing stage. Their core therapeutic effects are most pronounced in the signal amplification and ulceration stages. Targeted modulation of inflammatory cascades and microbial invasion during these stages is of crucial significance.

Other Functional Polymeric Materials-Based Micro-Nano Devices for OM Treatment

First, medical sponges fabricated from high molecular functional materials such as gelatin, chitosan, or alginate, characterized by their highly open and interconnected porous network structures, exert a positive influence on optimizing the local microenvironment. This structure can not only rapidly absorb and retain excessive exudate from the wound surface via physical mechanisms like capillary action, thereby maintaining a moist microenvironment that is conducive to cell migration and proliferation, but also effectively prevent secondary damage resulting from exudate accumulation.¹³⁹ Simultaneously, owing to its excellent plasticity, the medical sponge can serve as an ideal flexible drug storage depot, capable of loading and achieving the controlled release of various therapeutic drugs.For example, Alagha et al demonstrated that by loading dexamethasone into collagen-chitosan sponges, they verified that this carrier could achieve sustained drug release and effectively inhibit the persistent inflammation induced by OM.¹⁴⁰ Additionally, sponges functionalized with chitosan oligosaccharides and hyaluronic acid also exhibited the capacity to actively establish an anti-inflammatory microenvironment through methods such as regulating macrophage polarization. Research has indicated that the application of sponges loaded with recombinant epidermal growth factor in canine oral soft tissue wound models can significantly enhance the healing kinetics and accelerate the re-epithelialization process.¹⁴¹ Notably, through the introduction of advanced functional materials such as MXene, medical sponges are transitioning from passive dressings to intelligent responsive platforms that integrate rapid hemostasis, efficient antibacterial properties, controlled drug release, and active wound healing promotion (Figure 12A).¹⁴²

Figure 12 (A) Schematic diagram of the preparation and application of an MXene-based smart sponge with photothermal-responsive functionality. Reproduced with permission from Ref.142 Copyright 2024, Elsevier. (B) Schematic illustration of nanofibers fabricated via electrospinning technology for the treatment of oral diseases. Reproduced with permission from Ref.143 Copyright 2025, with permission from Bentham Science Publishers.

It is noteworthy that traditional medical sponges are prone to swell excessively, causing strong foreign body sensation, which further aggravates dysphagia and even poses a risk of suffocation. In contrast, the clot-like pore-gradient nanofibrous sponge with dual functions of “external filtration/internal adsorption” developed by Zhou et al is more appropriate for the treatment of OM, especially for grade 3–4 lesions accompanied by massive inflammatory exudate. The outer layer of this sponge is characterized by a relatively dense pore structure which can impede saliva erosion and prevent unregulated swelling. Meanwhile, the inner layer possesses interconnected macropores with high adsorption capacity, which can safely handle large volume of inflammatory exudate while maintaining structural stability. This dual-functional design not only addresses the issues of traditional sponges in the confined oral environment, but also provides a novel framework for the development of safe and effective oral sponges that can precisely adapt to the dynamic oral microenvironment and enhance patient compliance.¹⁴⁴

Secondly, electrospinning technology is capable of fabricating three-dimensional fiber networks characterized by a high specific surface area, high porosity, and a biomimetic extracellular matrix topological structure.¹⁴⁵ This carrier system not only has the capacity to efficiently load and stably safeguard bioactive molecules but also can realize intelligent responsive drug release via rational material design, thereby forming a composite interface with both long term physical barrier and precise drug delivery. The entire process of electrospinning technology and its application scenarios in oral treatment are presented in Figure 12B.^143,146 For instance, through the construction of core-shell structure fibers, the active ingredients can be encapsulated within the core and protected by the shell layer, achieving zero-order kinetic sustained release over several days.¹⁴⁷ The introduction of pH-sensitive materials enables the targeted pulsed release of the drug in the inflammatory microenvironment (with a weakly acidic pH).¹⁴⁸ Among these, coaxial electrospinning technology serves as the core approach for fabricating core-shell structured fibers, offering an ideal platform for the delivery of bioactive factors. Jiang et al designed a coaxial electrospinning method, in which the core-shell structure can effectively encapsulate and protect biologically unstable molecules, achieve precise programming of release kinetics through material regulation, realize sustained drug release, and actively regulate the tissue repair process.¹⁴⁹ Additionally, Zhou et al developed a coaxial electrospinning technique with mucosal adhesion properties, which can significantly extend the local retention time of the drug. This approach overcomes the limitations of traditional dosage forms, such as rapid clearance and frequent administration caused by saliva flushing. Simultaneously, it actively promotes tissue regeneration as an active factor carrier.¹⁵⁰

Finally, three dimensional (3D) printing technology, founded on the layer-by-layer accumulation principle of additive manufacturing, offers an individualized solution at the level of precise medical care for the treatment of OM (Figure 13A).¹⁵¹ This technology can accurately fabricate personalized scaffolds that precisely match the shape of the affected area using biocompatible materials, relying on the highly accurate digital 3D model of the patient’s oral cavity. Yu et al demonstrated that the embedded 3D printing technology realizes precise control of the drug loading amount and the gradient distribution of functional substances by parameterizing the filling patterns and nozzle sizes.¹⁵² It has achieved precise control of the drug loading capacity and the gradient distribution of functional substances, providing engineering and technical support for the on demand customization of personalized oral mucosal adhesion membranes. Based on this, the multi material 3D printing technology can construct smart scaffolds with functional zones.¹⁵³ For instance, the outer layer is constructed with hydrophobic and slow release antibacterial materials to form an anti-infection barrier, while the inner layer integrates hydrophilic hydrogels loaded with growth factors to promote mucosal regeneration (Figure 13B).¹⁵⁴ For instance, Tagami et al successfully developed a drug loaded ionic liquid/methacrylic acid polymer mucosal adhesion membrane via pressure assisted micro-injection 3D printing technology, achieving a breakthrough optimization in drug solubility and drug release in response to the inflammatory microenvironment (Figure 13C).¹⁵⁵

Figure 13 (A) Overall process of 3D printing technology for personalized oral therapy. Reproduced from Ref.151 Copyright 2022, Springer Nature. (B) Schematic diagram of a functionally zoned multilayer adhesive oral film structure. Reproduced from Ref.154 Copyright 2022, Springer Nature. (C) Schematic illustration of applying a 3D-printed film to an oral mucositis site, and structure of a multilayer film consisting of an IL-loaded layer and an HPMC-based supporting layer. Reproduced from Ref.155 Copyright 2022, MDPI.

To enhance readability, we have summarised the pathological characteristics of OM mentioned in this paper, along with the design requirements for functional polymeric materials and typical case studies (Table 1).

Table 1 Relationship Between OM Pathological Mechanisms and Functional Polymer Materials

Limitations and Future Perspectives

Functional polymer materials offer a variety of solutions for preventing and treating OM. Each type of material has its own unique advantages and limitations. Firstly, hydrogels possess excellent biocompatibility, enabling controlled drug release in response to multiple stimuli and integrating multiple therapeutic functions. However, some responsive systems have operational limitations in clinical settings, and the encapsulation efficiency of poorly soluble drugs is relatively low. Secondly, patch exhibits excellent wet adhesion and mucosal retention properties, enabling minimally invasive drug delivery to deep mucosal layers. However, conventional patches struggle to achieve effective drug release in deep tissues. Moreover, it is difficult to precisely control the mechanical strength of the microneedle tips of microneedle patches, which substantially influences drug release efficiency due to variations in the dynamic oral microenvironment. Subsequently, micro-nano DDSs exhibit significant performance complementarity and application limitations in mucosal drug delivery. The micron-based DDSs, with its excellent mucosal adhesion properties, can achieve sustained drug release. However, their particle size limits their ability to penetrate the mucosal epithelial barrier and lacks flexibility in drug loading strategy design and drug release kinetics regulation. The nano DDSs, leveraging the advantages of the nano scale, can efficiently penetrate the mucosal barrier, significantly enhancing the targeted delivery efficiency and bioavailability, and effectively overcoming the dissolution and delivery obstacles of hydrophobic drugs. However, their mucosal retention time is relatively short, and the long-term biological safety, immunogenicity, and in vivo metabolic fate of some nano carrier materials still need to be verified through systematic preclinical and clinical studies. In addition, medical sponges can efficiently absorb exudate from wound surfaces and have a high drug loading capacity. However, their interfacial adhesion strength and inherent mechanical strength are insufficient., making them prone to displacement or structural failure in the dynamic oral environment, which affects the continuity of treatment. Electrospun membrane with biomimetic structures, not only support microenvironment-responsive drug release and cell behavior regulation, but also promote tissue integration. However, their mechanical integrity and mucosal interface bonding strength are limited. Furthermore, functional modification is highly sensitive to the spinning process parameters, restricting reproducibility and large-scale application. 3D printing can fit the lesion site precisely and achieve personalized design of drug loading and functions. However, its preparation process is complex, time-consuming, and costly. The synergy between the material degradation kinetics and the oral mucosa regeneration process still needs to be improved through systematic optimization of the material-biological interface.

Given the various challenges faced by functional polymer materials,as mentioned above, the treatment of OM requires strategies to be formulated from multiple aspects, such as material design, carrier construction and clinical translation. In terms of material design, intelligent dynamic adaptive polymer systems with multiple microenvironmental response capabilities such as pH, enzymes, and redox should be developed. Furthermore, the biomimetic wet adhesion mechanism of mussels and the principle of tissue self-repair should be integrated to collaboratively optimize the interface adhesion strength, mechanical strength, and degradability of the materials, in order to adapt to the oral physiological environment and the drug release requirements of OM at different pathological stages. In terms of carrier construction, it can be designed based on core-shell, layered or gradient micro-nano structures to construct a multi-drug co-delivery platform comprising spatially separated drug-loading chambers and programmable controlled-release channels. This effectively avoids compatibility conflicts between drugs and enables temporally controllable synergistic release kinetics. In terms of clinical translation, it is essential to enhance the deep cross-disciplinary collaboration among materials science, oral medicine, oncology and pharmaceutical engineering, integrate advanced manufacturing technologies such as microfluidic chips, electrospinning and 3D bioprinting, in order to optimize the scalable production process and establish a complete chain of quality control standards; Simultaneously, by simplifying the administration operation procedures, reducing the foreign matter sensation of materials and improving patient comfort, the clinical applicability, safety and patient compliance of the treatment regimens can be significantly enhanced, thereby accelerating the efficient translation of basic research findings into clinical practice.

It is noteworthy that with the evolution of artificial intelligence (AI) technology, the profound integration of AI and the design of functional polymer materials is propelling a substantial transformation in the research paradigm of this field, offering a completely novel approach for realizing precise, efficient, and intelligent material research and development.¹⁵⁶

First, the AI conducts dynamic analysis of clinical images, pathological omics data, and biomarker data via deep learning algorithms. It constructs a multi-parameter coupled model to precisely identify the pathological stage of OM and enables the materials to realize dynamically responsive drug delivery.¹⁵⁷ For instance, through the analysis of wound characteristics including size, depth, and severity of infection, personalized material design is facilitated to achieve intelligent drug delivery.¹⁵⁸ Second, AI can be integrated with intelligent sensing technology to implement realtime monitoring of the wound-healing process of OM.¹⁵⁹ By continuously monitoring the key physiological indicators of the OM area, such as temperature, humidity, pH value, and the dynamic changes in inflammatory factor concentrations, the polymer carrier can achieve locally responsive drug release and mitigate systemic risks.¹⁵⁹ Finally, by analyzing the data generated by these sensors, the AI can assess the effectiveness of the treatment based on functional polymeric materials and provide data support for strategy adjustments.^159–161

In a word, with the accumulation of more experimental data, AI-driven functional polymeric materials are anticipated to emerge as a crucial approach for the personalized treatment of OM patients.

Conclusion

In conclusion, this review elucidates the pivotal role of functional polymeric materials in advancing the prevention and treatment of OM. By counteracting the disruption of oral microenvironment homeostasis induced by radiotherapy or chemotherapy, which includes xerostomia, dysbiosis, inflammatory cycles, and oxidative stress, and surmounting the rapid drug clearance in the dynamic oral cavity, these materials present customized therapeutic strategies. Among various materials, hydrogels show considerable promise due to their biocompatibility, mucosal adhesion, and ability to provide controlled drug release in response to local conditions. Additionally, micron- and nano-patches or DDSs enable localized, sustained, or targeted therapy, enhancing drug retention and bioavailability. Integration with AI-driven sensing and data analytics further facilitates real-time monitoring and personalized treatment design. Future efforts should prioritize clinical translation and interdisciplinary collaboration to realize precision, patient-centered OM management with enhanced efficacy and safety.