Targeted repair of oral mucosal injury: emerging applications of biomaterials-based drug delivery systems

Abstract

The oral mucosa, as an important barrier to external exposure, is susceptible to damage caused by various factors, leading to a series of clinical symptoms. Traditional treatment methods have problems such as short drug retention time and unstable local exposure, which make it difficult to meet the treatment needs of oral mucosal injuries. Biomaterials-based drug delivery system can significantly improve the local residence time, permeability and bioavailability of drugs through ultra-small particle size, surface modification and controllable release characteristics, and provide precise targeted therapy. This paper summarizes the application of biomaterials-based drug delivery system in oral mucosal injury, and analyzes its advantages in multi-stage collaborative treatment, including prevention of disease, effective treatment and promotion of rehabilitation. Although the current biomaterials-based system has made some progress in improving treatment effect and patient compliance, it still faces challenges such as long-term safety and manufacturing differences. In the future, biomaterials-based drug delivery system is expected to become an important tool for the treatment of oral mucosal diseases and play an important role in clinical practice.

Graphical Abstract

Introduction

As a key barrier against the external environment, the structure and function of the oral mucosa are essential for maintaining local homeostasis[1]. The oral mucosa is easily affected by trauma, infection, immune disorders and other factors, leading to loss of barrier function, inflammation, and tissue damage. By cause, oral mucosal injury can be classified as treatment related, such as radiotherapy induced oral mucositis (RIOM), or chemotherapy-induced oral mucositis (CIOM), and non treatment-related, such as recurrent aphthous stomatitis (RAS), infectious mucositis, and malignant tumor. These conditions are common, present with complex symptoms, often have a prolonged course, and significantly reduces the quality of life of patients. Epidemiological evidence suggests that oral mucositis (OM) is one of the most concerning toxicities of anticancer treatment. It affects over 75% of high-risk patients receiving chemotherapy or head and neck radiotherapy, and the reported incidence in patients treated with chemoradiotherapy for head and neck tumors ranges from 59.4% to 100%[2, 3]. Severe OM can cause marked pain and dysphagia, may limit oral intake, and is linked to unplanned treatment breaks and higher health care costs, which can compromise tumor control and patient survival. RAS is one of the most common oral mucosal diseases worldwide and is characterized by recurrent, painful ulcers. Population-based data suggest a mean prevalence of about 20% in the general population[4]. Although a single ulcer is usually self-limited, frequent recurrence, severe pain, and limits on eating and speaking can markedly reduce quality of life, and there is still no curative treatment. Malignant disease further adds to the overall burden of oral mucosal disorders. Oral squamous cell carcinoma (OSCC) accounts for more than 90% of oral cancers. In 2020, about 377,713 new OSCC cases were reported worldwide, and the global burden is expected to increase in the coming decades[5].

Currently, the treatment of oral mucosal injury still relies mainly on local medications. However, in the highly dynamic oral environment, continuous saliva flow and routine activities such as swallowing, chewing, and speaking can rapidly wash a formulation away. In addition, the non-keratinized epithelium and dense microbial biofilms create extra barriers. As a result, conventional formulations often have poor site targeting, short local residence time, limited control over drug release, and low bioavailability. Long-term use of some agents may also cause fungal infection, mucosal atrophy, and even systemic adverse reactions, further limiting the stability and sustainability of efficacy[6, 7].

In this context, biomaterial-based drug delivery systems offer a practical way to overcome key pathophysiologic barriers of the oral mucosa. With careful structural and interfacial design, platforms such as lipid nanoparticles, polymeric nanoparticles, nanomicelles, hydrogels, microneedles, metal nanoparticles, and electrospun nanofibers can improve mucoadhesion and prolong local retention in the wet, easily washed oral setting. These systems can also support high drug loading, improve mucosal permeation, and enable controlled or stimulus-responsive release. For example, drug-loaded nanostructured lipid carriers dispersed in a mucoadhesive buccal hydrogel showed nanoscale particle size, a low polydispersity index, and efficient drug entrapment, and helped extend mucosal residence and provide sustained release[8]. Basahih et al. loaded a poorly soluble antidiabetic drug into nanomicelles and formulated a unidirectional release buccal film. Compared with a film without the nanocarrier, the nanocarrier-loaded film increased buccal permeation and systemic exposure, further supporting the value of high-loading nanoplatforms for transmucosal delivery[9].Importantly, these biomaterial platforms are highly tunable and can be adapted to different causes and disease stages, enabling full-course strategies for oral mucosal disease-from prevention and symptom relief to tissue repair.

In summary, given the high incidence and recurrence of oral mucosal injury, the clear limits of conventional therapy, and the growing evidence for biomaterial-based delivery, a systematic evaluation is needed to clarify how these technologies can support full-course management. Therefore, this review summarizes biomaterial delivery systems used across different oral mucosal injuries, assesses their potential for clinical translation and key challenges, and discusses an emerging model of oral mucosal care centered on prevention, treatment, and recovery.

Oral mucosa injury

Inducement and pathological mechanism of oral mucosal injury

Predisposing factors

Treatment related mucosal injury is mainly seen after radiotherapy, chemotherapy and surgery, especially in patients with head and neck cancer. RIOM and CIOM are common and often severe, presenting with pain, ulcers, dysphagia, and malnutrition. In patients with head and neck malignancies treated with concurrent chemoradiotherapy, oral mucositis was reported in 91% of patients, and 66% had severe (grade 3–4) mucositis[10]. Reports indicate that more than half of severe cases show mucosal atrophy, ulceration, and altered oral microbiota[11], which seriously affects treatment adherence and quality of life. In addition, mechanical factors in dentistry, such as ill-fitting dentures, orthodontic appliances or damaged restorations, can cause traumatic mucosal injury[12]. Large mucosal defects after tumor resection or maxillofacial trauma tend to scar during healing, resulting in limited mouth opening and problems with eating and speech[13]. For non treatment-related injuries, although the oral mucosa heals faster and has a weaker inflammatory response than skin[14], in metabolic disease this advantage is often offset by hyperglycemia, accumulation of advanced glycation end products (AGEs) and elevated reactive oxygen species (ROS), resulting in delayed wound healing and a higher risk of infection[15, 16]. RAS is a common cause of oral ulcers. It is marked by recurrent painful superficial ulcers on the lips, tongue, or other oral mucosal sites, and involves multifactorial immune mechanisms[17, 18]. It not only destroys the mucosal barrier, but also is related to potential malignant diseases[19].

In addition, as the second largest microbial ecosystem of the human body, When host defenses decline, the flora can become imbalanced, such as Porphyromonas gingivalis, Candida albicans and other pathogenic bacteria can induce inflammation and contribute to local and systemic disease[20, 21]. On the other hand, about 90% of oral cancers are OSCC, and its incidence has risen in recent years. OSCC impairs appearance and oral function of patients, which significantly affected the quality of life. Oral potential malignant disorders (OPMDs), such as leukoplakia, erythroplakia and oral submucous fibrosis, are important precursors of OSCC. The risk of invasive oral cancer in OPMDs is significantly higher than that in healthy mucosa, and epithelial dysplasia is often found in histology[22, 23].

Pathological mechanism

Oral mucosal injury is a multistep, interconnected process, which can be summarized as initiation, amplification, imbalance and failed repair (Fig. 1). First, the damage usually begins with the distruction of the epithelial barrier. The abnormal differentiation of keratinocytes and the damage of connexins weaken defense against pathogens and mechanical stress[24]. Under physiological conditions, cells regulate stress by sresponses by releasing cytokines and growth factors[25]. However, the infection of bacteria and viruses destroyed these structures, increased the permeability of the barrier, and further worsens the barrier failure. Connexin 43 (Cx43) is a major gap-junction protein that mediates intercellular communication and maintains epithelial homeostasis. Downregulation of Cx43 is associated with early stages of malignant transformation[26–28].

Fig. 1.

Common causes and pathological mechanisms of oral mucosal injury

Next, the amplification of oxidative stress and inflammation worsens the injury. Excess ROS not only causes DNA damage, but also degrade the extracellular matrix[29]. Oral fibroblasts senescence and sustained release of ROS under stress, while keratinocytes apoptosis and ulcer formation[30]. ROS and inflammation amplify each other, activate NF-κB, MAPK pathway and inflammasome, which promotes the maturation of IL-1β and IL-18, and then aggravate inflammation[31]. Persistent inflammation also delays repair and increases the risk of cancer[32].

The changes in the oral microecology are central to the imbalance phase. Radiotherapy and immunosuppression promote biofilm formation by pathogens, increase drug resistance and inhibit healing[33]. This remodeling of microecology and metabolism further contributes to mucositis and delayed healing[34]. Despite the strong regenerative capacity of the oral mucosa, the repair response may be insufficient to achieve complete healing[35, 36]. However, disease, inflammation or surgical factors impair wound closure[37, 38].

In conclusion, oral mucosal injury is a complex network driven by multiple mechanisms. This suggests that clinical management should cover prevention, treatment, and rehabilitation. For example, the prevention phase aims to strengthen the barrier function and reduce invasion of pathogens, treatment phase needs to effectively control inflammation and oxidative stress, while the rehabilitation phase should promote tissue repair, accelerate healing and restore function. This multistep, coordinated strategy provides a practical framework for the treatment of oral mucosal injury.

Traditional treatment methods and their limitations

Traditional oral therapies, such as gargle, spray and patch, often have short residence time, difficult to maintain local drug concentration and uncontrollable release. Although the Mouthwashes is convenient, salivary dilution and swallowing shorten contact time, and many formulas contain ethanol or other excipients that can irritate the mucosa and reduce tolerance[39]. The antibacterial agents represented by chlorhexidine can be effective, but they often lead to taste changes, tooth staining and mucosal discomfort[40].

Conventional patches cover lesions frequently detach after a single application, and most active components remain on the mucosal surface with limited penetration[41]. Local analgesic and anti-inflammatory gargles can quickly relieve symptoms, but the effect window is short and does not alter the disease course.

Although topical corticosteroids have certain curative effect, they show poor retention and insufficient controlled release; long-term use may increase the risk of opportunistic infections[42]. Probiotics mostly provided as lyophilized tablets or lozenges, and the efficacy is often inconsistent due to delayed rehydration, loss of viability and unstable adhesion. This limitation is mainly tied to formulation and the lack of delivery system[43]. Natural active substances such as curcumin have poor solubility and stability, and are eprone to degradation. Without mucoadhesion and controlled-release design, it is difficult to ensure stable local exposure and efficacy.

In conclusion, traditional oral approaches face shortcomings in residence time, concentration maintenance, release control, and tissue penetration, and the stimulation and inconvenience of excipients also weaken the compliance. Antibacterial, analgesic, hormone and other strategies mainly offer short-term relief, while probiotics and natural active substances are constrained by poor stability and the lack of adhesive, controlled-release systems. Future delivery designs should align with the full treatment course, enhance mucoadhesion and stability early, improve penetration during active treatment, and enable sustained, precise release. On-demand controlled-release may strengthen long-term efficacy, support more stable outcomes during rehabilitation, and improve adherence.

Biomaterials-based drug delivery system

Design principle of biomaterials-based drug delivery system

As an open and highly dynamic environment, the complex physical and chemical composition of the oral cavity has brought significant challenges to local drug therapy, and has become the primary factor affecting drug absorption. The continuous flow of saliva is one of the key factors. Salivary water, enzymes, and ions not only dilute the drug, but also alter the solubility and stability of the drug, accelerate drug clearance, and markedly shorten residence time on the oral mucosal surface[44–46].

Secondly, the heterogeneity of oral mucosa structure determines regional differences in penetration. For example, non-keratinized regions such as the sublingual and buccal mucosa favor absorption because of rich blood flow and high permeability, while keratinized mucosal barriers such as the hard palate and gingiva limit drug entry[47]. Tight, adherens, and gap junctions further reinforce these barriers and restrict transmembrane diffusion, especially in the areas with a well-developed cornified layer. Mechanical movement in the mouth accelerates the removal of drugs from targeted sites, significantly reducing the persistence and stability of local dosing. In addition, the dynamic fluctuation of oral pH also influences the release and absorption of drugs, especially during inflammation or infection, when local pH decline will change the ionization state, solubility and permeability of drugs[48, 49].

The emergence of biomaterials-based delivery system provides a new approach for disease management. Its core is to construct nano carriers to improve drug targeting and utilization, and ensure the continuity and stability of treatment to adapt to different treatment stages. Therefore, to address the physiological barriers and environmental constraints of oral delivery, relying on the ultra-small particle size, high surface-area-to-volume ratio and tunable surface chemistry, these systems can traverse the multilayer oral mucosa and enter cells, increasing the penetration ability and prolonging the drug residence time. By embedding stimulus-responsive, controlled-release mechanism, it can achieve sustained release and more precise targeting, enhancing drug efficacy, reducing the frequency of drug administration and reducing adverse reactions. Compared with traditional formulations, biomaterials-based delivery system shows better penetration, longer action, and improved tissue targeting in the treatment of oral ulcer, mucositis, postoperative wound and precancerous lesions, and significantly improves the treatment effect and patient compliance.(Fig. 2).

Fig. 2.

Biomaterials-based drug delivery systems commonly used in oral mucosa and their advantages

In conclusion, biomaterials-based drug delivery system can not only break through the limitations of the traditional drug delivery system, but also provide a new solution for the multistage, coordinated treatment of oral mucosal diseases. It shows strong potential for basic research and clinical translation and may become important tools for future oral therapies.

Biomaterials-based drug delivery system for oral mucosa

In this section, systematic classification and functional analysis of biomaterials-based drug delivery systems commonly used in oral mucosa will be carried out based on material types and structural configurations.(Table 1).

Table 1.

Nanomaterials-based drug delivery system for the Oral Mucosa

Type	Representative	Features	Preparation method	Applications	Advantages	Limitations	Ref
Lipid-based drug delivery systems
Liposomes	Phospholipid vesicles	Co-encapsulate hydrophilic and hydrophobic drugs; biocompatibility	Thin-Film hydration (TFH) method; Detergent removal Method; Solvent injection method	Improve solubility and stability of poorly soluble drugs	Clinically studied; biocompatible; self-assembling; accommodate Macromolecular drug; surface-modifiable	Limited encapsulation efficiency; rapid clearance and short circulation; risk of membrane leakage; cost and process complexity	[50]-[51]
SLN	Solid lipid matrix	Enhanced drug stability and sustained release	High pressure homogenization (HPH); Hot or Cold homogenization; Solvent emulsification /evaporation; Supercritical fluid extraction of emulsions (SFEE); Ultrasonication or high speed homogenization	Improve solubility/stability of poorly soluble drugs	Drug protection; modifiable; scalable manufacturing; biocompatible and biodegradable	Lower loading; drug expulsion during storage; initial burst release	[53]
NLC	Solid–liquid lipid blend	Imperfect matrix creates voids for high loading		Improve solubility of poorly soluble drugs; controlled release	Higher payload; reduced crystallization-induced expulsion; tunable release; surface-modifiable; scalable	Prone to clearance; potential toxicity	[54]
Polymer-based drug delivery systems
Encompassing synthetic polymers	PEG; PLGA; PLA; PCL	Degradable, structurally stable; programmable release profiles	Solvent evaporation; Emulsification/solvent diffusion; Emulsification/Reverse Salting-Out; Nanoprecipitation	Stable controlled release; prolonged circulation	High stability; easy to prepare	Degradation products require evaluation	[57]-[58]
Natural polymers	CS; HA	Cationic adsorption; receptor affinity; water retention and film-forming		Mucoadhesion, targeting, pro-healing	Prolonged residence; tissue targeting; promote repair	Batch variability in performance	[57, 59]
Self-assembly of amphiphilic block copolymers	Micelles; Polymersomes	Prolong local exposure; periodic release	Direct dissolution; Dialysis; emulsification and solvent evaporation; Thin-film hydration; Freeze-drying; Powder hydration method; Solvent switch method	Increase tissue penetration; lower potential toxicity; integrate stimuli-responsive modules for controlled release	Easier release control; lower batch-to-batch variability	Assembly stability varies; risk of premature release; EPR dependence and tissue heterogeneity; interbatch differences	[61]-[66]
Gel systems
In situ gel	Thermo-, ion-, or pH-responsive	Phase transition triggered by temperature, ions, or pH; form a local barrier	Cold method	Analgesia, anti-inflammation, mucosal protection; filling post-operative defects	Strong adhesion; Extend local retention; improved bioavailability; fewer systemic adverse effects; convenient dosing;relatively simple preparation	Delayed onset and lower peak; varying degree of initial burst; tolerability needs assessment	[68]-[69]
Hydrogels	Natural or synthetic	3D porous network; ECM-mimetic; tunable loading and diffusion	Physical cross-linking; Chemical cross-linking	Local controlled release; tissue repair and wound healing; minimally invasive diagnostics	Good compatibility and degradability; robust mechanics and structural stability; theranostic potential	Natural: batch variability; Synthetic: degradation and long-term safety to be assessed	[70]-[72]
Nanogels	Cross-linked polymeric nano-networks	Small size, high surface area; surface functionalization and targeting; partial protection from enzymatic degradation	Physical cross-linking; Chemical cross-linking; Microfluidic-Assisted Fabrication; 3D printing	Carry labile or fast-cleared drugs; long-term therapy in chronic disease	Enhanced mucosal penetration; sustained release; intracellular targeting feasible	Microenvironment heterogeneity may destabilize release; scale-up variability	[73]-[74]
Microneedles
Solid microneedles	Metal or high-strength polymer needles	Poke and Patch	Laser ablation, micro-molding; Additive manufacturing; Injection molding; Chemical isotropic etching; Surface/bulk micromachining; Lithography-electroforming-replication	combined with topical formulations	Increased permeability; extensible area; Easy to manufacture	Risk of toxicant permeation or infection; secondary dosing depends on technique	[76]-[78]
Hollow microneedles	Needle channel	Bolus or continuous infusion; rapid push or slow drip; direct delivery to superficial tissues		Load proteins, vaccines, nucleic acids	Quantitative dosing; rapid onset; programmable dose and rate	Complex fabrication; clogging risk; clinical optimization of site and patching needed	[79]
Coated microneedles	Drug coated on needle surface	Release upon application; simple to prepare		Load vaccines, small molecules	Rapid release; good adherence; immunologic benefits	Limited loading; drug compatibility constraints; coating uniformity and delivery efficiency vary	[80]-[79]
Dissolving microneedles	Water-soluble polymers	Dissolve and release concurrently; high replication fidelity		Load vaccines and biologics	Minimally invasive, low pain; no sharps waste; good safety; high adherence; strong immune effect	Need to balance strength and stability; dose limited by needle volume and formulation	[81]
Metal-based drug delivery systems
Noble metals	AuNPs、AgNPs	Good biocompatibility; facile surface modification	Top-down (dispersion) approach; Bottom-up (condensation) approach	Imaging, antibacterial therapy, drug delivery	Theranostic integration	Local accumulation; long-term safety requires evaluation	[82]
Transition- metal oxides	Fe3O4NPs	Magnetic responsiveness; imaging		Targeted enrichment, tissue imaging, drug delivery	Magnetic navigation; image-guided localization	Local aggregation; oxidative stability	[83]-[84]
Other functional metals/alloys	Cu-Ag、MOFs	High surface area and tunable pores; high loading, on-demand release		Antibacterial and anti-inflammatory; combination therapy	Broad antimicrobial spectrum; promote healing	Ionic dose and toxicity window require control	[85]-[86]
Other systems
Nanofibers	PVA; polydioxanone-halloysite nanotubes	High surface area; tunable pore size	Electrospinning	Local dressings, regenerative scaffolds, controlled release	Conform to mucosa; high loading; pro-regenerative	Scale-up and batch consistency remain challenges	[87]-[89]
FNA	DNA tetrahedra, hexahedra	Highly programmable; nuclease-resistant	Structural nanotechnology and dynamic nanotechnology	Precision delivery; tissue repair	Multi-target functionalization; good compatibility	Manufacturing cost; in vivo stability	[90]-[91]
Core–shell nanocarriers	Hydrophobic core with hydrophilic shell	Multishell layers to tune release kinetics	Exploit the chemical properties of the molecules to self-assemble	Dual compatibility; stable controlled release	Improved penetration and bioavailability	Process complexity	[92]
Clay-based nanomaterials	Montmorillonite, bentonite, kaolin, aminated clays	Lamellar structure; ion exchange; swelling	Intercalation; Organomodification; Lumen loading; Delamination/Exfoliation	Antibacterial, anti-inflammatory, analgesic controlled release	Good adhesion; high stability; low cost	Possible side effects; long-term safety requires assessment	[93]-[94]

Lipid-based drug delivery systems

Lipid-based nano delivery systems include nanoemulsions, self emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and liposomes. Classical preparation methods include the thin-film hydration method, microfluidic methods, high-pressure homogenization, and the microemulsion technique. These methods can affect key quality attributes such as particle size, lamellarity, encapsulation efficiency, residual solvent, and batch-to-batch reproducibility[50, 51]. Among them, liposomes, as the early representative of LNPs, are vesicles with unilamellar or multilamellar phospholipid bilayers that can encapsulate both hydrophilic and hydrophobic drugs. Liposomes have been widely used in anti-tumor and anti infection, and support targeted and controlled release. However, there are still some problems such as insufficient membrane stability, rapid clearance by reticuloendothelial system, high cost of scale-up, and the need for organic solvents in some preparation processes[52].

To address these issues, a new generation of LNPs has has been developed, including SLNs and NLCs. Compared with liposomes, SLNs are often described as more physically stable and can provide sustained drug release. However, the highly ordered crystalline lipid matrix may limit drug loading, and drug expulsion during storage and an initial burst release have been reported[53]. NLCs address these limits by incorporating liquid lipids into the solid matrix, which creates a less ordered structure that can increase drug loading, reduce crystallization-related drug expulsion, and allow a more flexible release profile, while maintaining the safety profile and scalable manufacture associated with SLNs. For example, Shah et al. reported that increasing the liquid lipid fraction from 5 to 15% (w/w) increased entrapment efficiency from 30.83 ± 2.39% to 74.78 ± 3.34%, and drug loading from 1.92 ± 0.12% to 4.02 ± 0.17%[54]. For formulation quality, many lipid nanocarrier studies use particle size ~ 200 nm and polydispersity index (PDI) ≤ 0.3 as practical targets for a stable dispersion, and surface charge is often tuned to be near-neutral or slightly negative to reduce nonspecific interactions and support longer circulation[55, 56].

Overall, owing to their biocompatibility and biodegradability, such platforms can improve drug stability and local exposure and are amenable to surface modification for targeting and penetration enhancement. They are now widely applied in the delivery of nucleic acids, small-molecule drugs, and vaccines, as well as in food and cosmetic formulations.

Polymer-based drug delivery systems

Polymer-based nano delivery systems are commonly grouped into three categories in general discussion, encompassing synthetic polymers, such as polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), and polyvinyl alcohol (PVA); natural polymers, such as chitosan (CS) and hyaluronic acid (HA); as well as micelles and polymersomes formed by the self-assembly of amphiphilic block copolymers. Common preparation routes include emulsification–solvent evaporation/extraction, double emulsion (W/O/W), and nanoprecipitation. The method chosen affects whether hydrophilic or lipophilic drugs can be loaded, and it can change encapsulation efficiency, particle size, PDI, residual solvent, and batch reproducibility[57]. Owing to their controllable molecular structure and degradability, synthetic polymers are often used to build stable frameworks and provide a long-cycle “stealth” effect, whereas natural polymers offer good biocompatibility, mucosal adhesion, and receptor targeting. For example, Zhang et al. prepared PEGylated liposomes. Compared with the free drug, conventional liposomes and PEGylated liposomes prolonged the plasma elimination half-life by approximately 5.8-fold and 17.5-fold, respectively, and increased Area Under the Curve by about 6.7-fold and 13.3-fold, suggesting that a PEG coating can extend systemic exposure[58]. In a thiolated N-triethyl chitosan (TEC-Cys) nanoparticle system reported by Rahbarian and colleagues, the mean particle size was ~ 127 nm with a PDI of 0.26, a ζ-potential of ~  + 24.6 mV, and an entrapment efficiency of ~ 98%. The positive surface charge is consistent with the known tendency of chitosan-based carriers to interact with negatively charged mucins via electrostatic attraction, which can support mucoadhesion and mucosal delivery[59].

Amphiphilic block copolymers can adopt diverse morphologies, including micelles, wormlike structures, and vesicles, by tuning the hydrophilic mass fraction, thereby balancing stability, drug loading capacity, and controlled-release performance[60]. Micelles have a low critical micelle concentration, slow dissociation, and adjustable size and morphology, making them suitable for loading hydrophobic drugs, and they can integrate stimuli-responsive modules to achieve long-term local exposure and periodic drug release. Importantly, the preparation route-such as direct dissolution, dialysis, emulsification-solvent evaporation, or thin-film hydration-can change the micelle self-assembly conditions and thereby affect micelle uniformity, drug loading, particle size, drug localization within the micelle, and kinetic stability[61]. Polymeric micelles are typically in the tens-of-nanometers range, and sizes around 20–100 nm are often used in tumor delivery to support passive accumulation via the enhanced permeability and retention (EPR) effect and to help maintain circulation. A low PDI is commonly used as a practical indicator of a narrow size distribution and batch consistency, and values ≤ 0.3 are often considered acceptable in nanoparticle dispersions. Surface charge is also tuned to reduce nonspecific interactions; near-neutral or slightly negative zeta potential is frequently used to limit protein adsorption and reduce rapid clearance by the reticuloendothelial system (RES), which can support longer circulation. For poorly soluble (hydrophobic) drugs, loading and retention in micelles depend largely on drug–polymer interactions and structural parameters of the block copolymer[62, 63].For example, Liu et al. prepared curcumin-loaded polymeric micelles with a mean diameter of 28.2 ± 1.8 nm, PDI 0.136 ± 0.050, drug loading of 14.84 ± 0.11%, and encapsulation efficiency of 98.91 ± 0.70%, in their report, the micelle formulation showed slower, sustained release and greater antitumor activity than free curcumin in a breast tumor model[64]. Polymersomes possess a double-layer membrane that can simultaneously encapsulate hydrophilic and hydrophobic drugs. they are taken up by endocytosis and disassemble in the cytoplasm. By regulating membrane stability and permeability, these polymersomes enable selective release in inflammatory and tumor microenvironment. In addition, surface functionalization can further enhance specific binding and cellular uptake[65, 66]. Common fabrication routes include thin-film hydration, solvent switch methods, and microfluidics. These choices influence vesicle structure, size distribution, and drug loading, which in turn affect permeability, release behavior, and cargo protection[67].

In conclusion, the polymer-based drug delivery system shows the comprehensive improvement of adhesion, penetration and controlled release performance under the combination of the advantages of synthetic and natural materials. Among them, micelles and polymersomes based on amphiphilic block copolymers have become an important research direction in the field of mucosa and precise drug delivery due to their programmable morphology, designable structure and integrable function.

Gel system

Over the past decade, gel drug delivery systems have become an important research direction for oral mucosal drug delivery due to their strong adhesion, controlled release, and markedly prolonged local residence time, typically including in situ gel systems, hydrogels, and nanogels. In situ gel is characterized by liquid administration and rapid gelation in vivo. After entering the mouth, it gels in response to physiological stimuli such as temperature, pH, or ion concentration, thereby maintaining a long residence time under salivary flow. It is easy to prepare, suitable for filling irregular defects, and supports local controlled release. Typical systems include thermo-responsive types, such as Pluronic F127 and PNIPAAm, which undergo gelation at body temperature (≥ 37 °C)[68], ion-responsive types triggered by Na⁺ and Ca²⁺ present in saliva and other bodily fluids, and pH-responsive types that leverage inflammatory acidification to trigger drug release[69].

Hydrogels are three-dimensional porous networks formed by physical or chemical crosslinking of hydrophilic polymers, which can mimic the extracellular matrix (ECM), have good biocompatibility, and offer drug-loading capacity and diffusional control, thereby reducing systemic exposure.These systems are typically prepared by physical crosslinking or chemical crosslinking. The crosslinking strategy can alter the network structure, swelling, and mechanical strength, and it also affects degradation and diffusion-controlled release[70]. By origin, they can be divided into natural, such as gelatin, CS, alginate, and synthetic, such as PVA, polyacrylamide (PAM). Natural hydrogels have biodegradability and low immunogenicity and are often used in tissue repair and wound healing. In contrast, synthetic hydrogels are more suitable as sustained release platforms due to their high mechanical strength and good stability. For example, in a proteolytic setting, an IK7–gelatin methacryloyl (GelMA) double-network hydrogel remained intact for at least 72 h and released ~ 15.4% of the peptide within 48 h. These data support mechanical stability and sustained release in a hydrated, enzyme-rich environment[71]. When combined with temperature, pH, ROS, and other stimuli-responsive mechanisms, hydrogels can support on-demand release, improving local bioavailability and dosing precision. Some systems have also been developed as non-invasive diagnostic tools, such as hydrogels for protein capture, labeling, and controlled release, which can be used for early screening of oral diseases[72].

Nanogels, which combine the flexible polymeric network of hydrogels with the permeability and targeting capabilities of nanoparticles (NPs). Typical nanogel particles typically range in size from tens to hundreds of nanometers, with uniform particle size and high water content, and can efficiently encapsulate enzymes, proteins, antibiotics, and antitumor drugs. Beyond conventional crosslinking routes, microfluidics and 3D printing have been highlighted as advanced approaches that improve control over material properties and support more scalable fabrication[73]. By tuning particle size and applying surface functionalization, nanogels can achieve targeted intracellular delivery. At the same time, their network structure protects the drug from salivary and tissue enzymes, thereby extending the pharmacodynamic effect, and they show lasting efficacy in chronic inflammation control and mucosal barrier repair. Huai and colleagues developed an oral ROS–responsive, creatine-modified selenium-based HA nanogel for colitis. The nanogel had a hydrodynamic size of ~ 160 nm and a PDI of 0.23; after creatine grafting, ζ-potential shifted from − 27.8 mV to − 19.8 mV, indicating that surface charge can be tuned by functionalization. The dispersion remained stable in phosphate-buffered saline (PBS) for at least 4 days, but degraded rapidly under acidic hydrogen peroxide, consistent with responsive breakdown in ROS-rich inflammatory sites[74].

Overall, within the complex oral microenvironment, gel-based systems not only enhance local efficacy and patient adherence but also provide a scalable platform for theranostic integration and precision therapy.

Microneedles

As a cross-mucosal delivery and sampling platform, the microneedle (MN) system has developed rapidly for drug delivery, local immunization, body-fluid collection, and biosensing because of its minimally invasive profile, low pain, site-specific application, and high delivery efficiency. MNs are commonly fabricated by micromolding, drawing, droplet-born air blowing, and 3D printing. The fabrication route affects geometric fidelity (tip sharpness and aspect ratio), mechanical strength, drug placement (surface coating, needle matrix, or hollow lumen), and batch-to-batch reproducibility[75]. The basic principle is to form temporary microchannels on the tissue surface with micron-scale needles, thereby bypassing the mucus and epithelial barriers and substantially improving permeation and local exposure while avoiding stimulation of nerve endings. At present, MNs have been used for local delivery of small molecules, proteins and antibodies, and nucleic acids, and have shown broad prospects in vaccination, oral cancer diagnosis and treatment, oral-ulcer management, and dental analgesia.

According to design and function, MNs can be divided into solid, hollow, coated, and dissolving microneedles. Solid MNs enhance local penetration by mechanically creating microchannels, and are then supplemented by topical preparations. By increasing needle shaft mechanical strength or using a roller design, drug loss can be reduced and the treated area expanded[76]. In vaccine delivery, solid MNs have been reported to elicit more durable and stronger humoral responses than intramuscular injection[77]. They have also shown efficient collection of oral epithelial cells and DNA for diagnostic sampling[78]. Hollow MNs incorporate lumenized channels to bypass surface barriers and directly release drug solution into superficial tissues, supporting one-time injection or controlled infusion. They are suitable for macromolecules such as proteins and vaccines, and enable precise delivery by adjusting aspect ratio, orifice size, and flow rate. Gupta et al. infused insulin intradermally in people with diabetes using a 900-µm hollow microneedle and compared it with a conventional 9-mm subcutaneous catheter. The microneedle shortened the time to peak insulin concentration, while the area under the insulin concentration (AUIC) was similar between groups, suggesting faster absorption without a meaningful change in relative bioavailability. Microneedle insertion was also less painful and caused less erythema, with faster local recovery[79].Coated MNs load drug onto the needle surface to achieve rapid release. The delivered dose is mainly determined by coating thickness and formulation concentration, and the method is simple and fast. They are easy to prepare and operate. In influenza vaccination, coated MNs have enhanced local immune responses and reduced viral replication[80]. In addition, they can provide a more lasting analgesic effect in local anesthesia applications [81]. Dissolving MNs are composed of water-soluble polymers. After insertion, they dissolve in interstitial fluid and release drugs concurrently, with the safety advantage of leaving no sharp instrument. Studies have shown that a dissolving microneedle influenza-vaccine patch achieved protective immunity superior to intramuscular injection, suggesting the feasibility of local mucosal biologic delivery[82]. In summary, MNs provide a promising platform for precision therapy and in situ diagnosis of oral-mucosal diseases, combining efficient tissue penetration, programmable release, and broad drug compatibility.

Metal-based drug delivery systems

Metal-based nanocarrier (MNPs) systems offer distinct physicochemical features, support multifunctional designs, and can be tuned through engineering. They have been explored for drug delivery, imaging, and therapy, and may be especially useful for local delivery in the oral cavity, where saliva turnover can shorten formulation residence time. The synthesis of MNPs is often described as two broad routes: a top-down (dispersion) approach and a bottom-up (condensation) approach. Based on composition, these systems can be broadly grouped into three categories. Noble-metal nanoparticles, such as gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs), are widely studied because their surface chemistry enables straightforward functionalization, which supports both drug loading and diagnostic readouts. For AuNPs, localized surface plasmon resonance (LSPR) can be tuned toward the near-infrared, providing strong optical contrast and enabling photothermal heating under irradiation[83]. After modification with thiol ligands or other adhesive groups, AuNPs can show stronger mucoadhesion, which may prolong mucosal retention and increase local exposure. Transition-metal oxides, such as Fe₃O₄ NPs, exhibit magnetic responsiveness and an engineerable interface, allowing magnetic guidance, enrichment, and controlled release under an external field. Concurrently, as MRI T2 contrast agents, they enable lesion localization and efficacy evaluation[84, 85]. In addition, metal–organic frameworks (MOFs), Cu-Ag composite nanostructures, and other emerging platforms leverage high specific surface area and tunable pores to achieve high loading and on-demand release. They can also respond to oral-specific cues such as pH and ROS, selectively releasing Ag⁺, Cu²⁺, Zn²⁺ ions to synergize antibacterial, anti-inflammatory, and pro-healing effects[86, 87]. In summary, metal-based nano delivery systems offer coordinated advantages in targeting, controlled release, image guidance, and local diagnosis-and-therapy within the oral cavity.

other systems

Nanofibers, functional nucleic acid nanostructures (FNA), core-multishell (CMS) nanocarriers, and clay-based nanomaterials can overcome the limitations of short mucosal residence, poor tissue penetration, and suboptimal release control in oral local therapy through engineered morphology and programmable release.

Nanofibers, with high specific surface area and a three-dimensional porous network, can not only improve drug solubility but also mimic the ECM to support cell adhesion, proliferation, and migration, thereby promoting tissue regeneration. Electrospun nanofibers used for drug delivery typically have diameters from tens to a few hundred nanometers. They offer high surface area, high porosity, and good flexibility, and these properties depend on the polymer and electrospinning conditions[88]. For example, Bhattacharjee et al. reported that electrospun composite nanofibrous scaffolds supported osteoblast-related responses and promoted new bone-like matrix formation, consistent with an ECM-mimicking microenvironment[89]. In addition, advances in electrospinning also allow control of fiber diameter, pore structure, and drug distribution, which supports dental regeneration and local controlled release. For example, electrospun scaffolds based on polydioxanone and halloysite nanotubes can promote regeneration of the pulp–dentin complex, and have the potential to be used as postoperative dressings[90]. FNA can self-assemble into tetrahedra, cubes, and related architectures using DNA or RNA, offering high programmability, biocompatibility, and structural stability. In oral wound settings, such structures have shown antibacterial, antioxidant, pro-angiogenic, and tissue-reconstruction potential[91, 92]. Core–shell nanocarriers rely on the synergy between a hydrophobic core and hydrophilic shell. A representative platform is the dendritic CMS design, which can improve oral-mucosal permeability and bioavailability and enable precise release by modulating shell structure[93]. Clay-based nanomaterials, such as montmorillonite, bentonite, kaolin, aminated clays, leverage their lamellar structure and high surface area to achieve controlled release via ion exchange and swelling, while enhancing mucoadhesion, stabilizing labile drugs and improving bioavailability, which are suitable for antibacterial, anti-inflammatory, and analgesic applications[94]. Lee et al. prepared an aminated organoclay composite system with a particle size of about 400 nm, a ζ-potential near -20 mV, and an encapsulation efficiency > 90%. In a Caco-2 model, it increased the apparent permeability coefficient (Papp) of insulin by about sevenfold. After oral dosing in rats, it enhanced colonic absorption and produced a longer glucose-lowering effect. These findings suggest that aminated clays can provide high loading and pH-responsive release, and that surface charge can be tuned to strengthen mucosal interactions for delivery to inflamed or tumor-associated mucosa[95]. Taken together, these emerging systems provide diverse tools and translational prospects for precise therapy of oral mucosal disease.

Overall, in oral mucosal delivery, differences across systems are more often shaped by both the oral environment and the manufacturing route. The evidence of head to head comparison of two types of systems under the same drug, the same model and the same evaluation index is still relatively limited. Using gels and microneedle systems as an example, gels mainly rely on physical or chemical crosslinking to form a network. Their crosslink density and swelling behavior can directly affect drug diffusion and how well the formulation stays adhered. In contrast, microneedles fix needle geometry through processes such as molding or casting, and they control drug distribution through surface coating or matrix loading. Their effect is closer to using microstructures to increase drug entry into the mucosa, rather than only prolonging surface contact. In a local anesthesia setting, a microneedle patch combined with lidocaine gel further reduced dental injection pain compared with a control patch, and no adverse events occurred [81]. This finding suggests that microneedles may enhance local permeability and increase the effective depth of a topical anesthetic. In a similar study, hydrogel-coated microneedles showed higher 48-h permeability than the hydrogel alone, supporting a clearer advantage when the goal shifts from surface coverage to deeper tissue exposure[96]. It is important to note that microneedles and gels are not opposing options; in practice, gels often serve as the drug reservoir, while microneedles act as a placement and penetration platform.

Likewise, differences among nanocarriers also depend strongly on the process route and the resulting key quality attributes. For example, comparisons of SLN and NLC highlight that both often rely on techniques such as high-pressure homogenization, while NLC designs that combine solid and liquid lipids can increase drug loading, improve release behavior, and enhance stability.In one of the few head-to-head studies, Dattani et al. compared polymeric micelles, liposomes, and SLN for paclitaxel delivery. SLN showed the slowest paclitaxel release and the highest stability, and it produced a significant delay in tumor growth versus the other carriers in a melanoma xenograft model[97]. In another same-drug comparison, liposomes achieved stronger bacterial inactivation than polymeric micelles in a photodynamic antimicrobial system[98], indicating that the relative merits of micelles and liposomes depend on drug targeting and mechanism of action. Therefore, comparisons across delivery systems should specify how the preparation process shapes key quality attributes and, in oral mucosal applications, should use measurable endpoints such as residence time, permeability, and release rate to define the suitable scope and limits of each system.

Progress in the application of biomaterials-based drug delivery systems in oral mucosal diseases

Treatment related mucosal injury

Radiotherapy-induced oral mucositis (RIOM), or chemotherapy-induced oral mucositis (CIOM)

RIOM or CIOM is initiated by oxidative stress and DNA damage, which activate NF-κB and related inflammatory transcription programs and amplify pro-inflammatory mediators, often accompanied by microvascular injury, local microbial imbalance, and immunologic suppression. Once lesions enter the ulcerative phase, healing generally proceeds via re-epithelialization. Current guideline-concordant measures such as reinforced oral hygiene, saline or sodium bicarbonate rinses, topical anesthetics or analgesics, oral cryotherapy, and photobiomodulation can relieve symptoms but are often limited by short mucosal residence, variable exposure, and adherence challenges. In this context, biomaterials-based drug delivery system provide additional options (Table 2) (Fig. 3A).

Table 2.

Biomaterials-Based Drug Delivery Systems for Radiotherapy or chemotherapy induced oral mucositis

Type	Representative	Features	Applications	Advantages	Ref
Polymer nanoparticles, micelles	Pluchea indica leaf extract NPs; Curcumin-micelles	Improve solubility and stability; enhance mucoadhesion; prolong local exposure	Anti-inflammatory; analgesic; increase local bioavailability	Good oral retention and adhesion; superior efficacy to conventional forms	[99]-[102]
Natural polymer mucoadhesive spray	Mucosamin®	Forms a mucoadhesive protective film	In vitro prevention of oxidative damage; potential clinical prevention of OM	Strong adhesion; antioxidant effect	[103]
In situ gel	Erythropoietin-gel; Benzydamine hydrochloride-CA; Col/HA-E/Alg; Fullerol thermogel; LBP thermogel	Rapid gelation at oral temperature; sustained release	Anti-inflammatory, antioxidant, pro-repair; durable barrier	Enhanced mucoadhesion; prolonged release	[104]-[108]
Nanogel	Chitosan-based oxepin nanogel; Omega-3 nanogel	3D hydrophilic network; high loading; local adhesion and sustained release	Anti-inflammatory, antimicrobial, antioxidant; analgesic; microbiome modulation	Multiple benefits shown in clinical studies	[109]-[110]
Self-assembled hydrogel	G-PVA hydrogel; Jati oral gel	Noncovalent self-assembly; structural stability; easy use	Anti-inflammatory; pro-healing	Strong mucoadhesion; sustained release; biocompatible; good clinical effect and adherence	[111]-[112]
Topical gel	Vitamin D gel	Local delivery; safe; combinable with standard care	Reduces severity and pain scores	Convenient, non-invasive; better local absorption	[113]
Biologic regenerative gel	PRF gel	Autologous; releases multiple growth factors	Promotes mucosal regeneration and healing	Simple; low immunogenicity; good safety	[114]
Metal nanoparticles	AuNPs, AgNPs	Surface modification improves biocompatibility and anti-inflammatory activity; synergy with polysaccharides/antioxidants	Accelerate ulcer closure; reduce secondary infection	Multimechanistic synergy; dual antibacterial/anti-inflammatory potential	[115]-[116]
Tetrahedral DNA nanostructures	Cur-TFNAS	High cellular uptake and stability	Potent anti-inflammatory effect; efficient uptake	“Nano-shield” strategy; safe, efficient, precise delivery	[117]

Fig. 3.

Drug delivery system for treatment related mucosal injuries. Main biomaterials-based drug delivery systems and their mechanisms of action in treatment related mucosal injuries. LBP ameliorates radiation-induced oral mucosal injury. (ⅰ) Representative images of oral ulcers for each group after irradiation and the calculated ulcer area in each group, (ⅱ) Immunohistochemical analysis of γ—H2AX expression in oral mucosa of control and LBP treated rats[108]. (ⅰ) Schematic diagram of G-PVA hydrogel for efficient treatment of radiation-induced oral mucositis. (ⅱ)Photos of mouse tongue, analysis of ulcer area, and appearance score. (ⅲ) IHC staining images of makrer IL-6 and IL-1b post-X-ray irradiation[111]. Flowchart of the experiment to repair defects in the buccal mucosa of rabbits, photographs of the gross observation of the defect and H&E-stained sections of the mucosal tissue in the defect area[118]. Reprinted with permission from Refs [108, 111, 118]

Polymer nanoparticles and micelles can improve solubility for poorly soluble drugs, enhance tissue permeation, and prolong local exposure. Clinical studies report that nanomicelles curcumin increase bioavailability and reduce inflammatory severity, thereby lowering oral mucositis (OM) grades[99, 100]. However, Ramezani et al. found no clear advantage of oral nanomicelles curcumin over curcumin mouthwash in a small trial, underscoring the need for larger, well-controlled studies[101]. Similarly, nanoformulation of plant extracts mainly aims to improve dispersion, stability, and mucoadhesion, which may improve local performance. In this study, nanoparticles loaded with Pluchea indica leaf extract were prepared using a solvent displacement method. The particles were kept in the nanoscale range with a narrow size distribution. Accelerated stability testing further suggested improved stability of the extract in an oral spray formulation, with added benefits such as higher apparent solubility, preserved activity, and sustained release. It is important to note that these studies support the feasibility of preparation and formulation stability, but evidence on mucosal residence time, the effective dose range, and long-term safety in clinically relevant OM settings is still limited and is mainly based on in vitro cell studies[102]. Another study reported that a spray formulation of HA enriched with amino acids (Mucosamin®) can form an adhesive physical barrier and provide moist protection on the mucosal surface. It also blocked H₂O₂-induced senescence and reduced the negative effects of fibroblasts on keratinocyte viability and migration. Clinical data suggest that preventive application can reduce the incidence and severity of OM[103].

Gel systems provide a hydrated microenvironment and high drug loading through a three-dimensional hydrophilic network. Stimuli-responsive in situ gels rapidly gel at oral temperature and under inflammatory acidification, creating a durable barrier and a local depot with anti-inflammatory, antioxidant, and pro-repair effects. Erythropoietin-loaded hydrogel, benzydamine hydrochloride-loaded chitosan gel, collagen-hyaluronic acid–alginate cross-linked gel (Col/HA-E/Alg), fullerenol thermosensitive gel and Lycium barbarum polysaccharide-glycoprotein (LBP) thermosensitive hydrogel[104–108] (Fig. 3B), not only alleviate OM and promote tissue repair but may also help stabilize the oral microbiota and reduce complications. For example, Zhao and colleagues developed a thermoresponsive gel system. The reported mean particle size (5.15 ± 0.74 nm) and a negative zeta potential suggest good dispersion stability in an aqueous phase, which supports sustained ROS scavenging. In release studies, the cumulative release exceeded 50% at 8 h and was near complete at 24 h. Oral fluorescence imaging suggested a relatively continuous local exposure. In vitro, the gel reduced radiation-related ROS signals and mitigated changes linked to DNA and mitochondrial injury. In vivo, it alleviated tissue injury in RIOM and helped maintain oral microbiota homeostasis[107]. Chitosan-based doxepin nanogel has shown analgesic, anti-inflammatory, and healing-supporting effects in clinical evaluation[109]. An omega-3 nanoemulgel combines an oil-in-water nanoemulsion with a biodegradable gel matrix, embedding lipophilic components as small droplets within a viscous base. The reported mean droplet size was 146.7 ± 11.45 nm with a low PDI, and the system remained stable without phase separation. After gel formation, it becomes a viscous formulation with some spreadability, which often supports film formation and mucosal retention in oral settings where longer residence time is needed. In head and neck radiotherapy patients, it showed anti-inflammatory and antioxidant effects and was associated with modulation of microbial balance[110]. For self-assembling systems, dual-functional guanosine-based (G-PVA) hydrogel and Jati (Jasminum grandiflorum) oral gels rely more on reversible covalent bonds and noncovalent interactions[111, 112] (Fig. 3C). They can flow temporarily under shear for easier spreading, then recover quickly after shear stops, and adhere firmly to the wet mucosa, which helps them tolerate oral rinsing and mechanical disturbance. Using a G-PVA supramolecular hydrogel as an example, it can rapidly return to a gel state under low strain after high-strain disruption, and it can recover part of its storage modulus over repeated cycles, consistent with a reconfigurable network. In vivo, it reportedly remained attached for more than 90 min after simulated rinsing and formed a uniform coating layer. Zeta potential, UV–vis, and FT-IR results supported multiple interactions with mucin, providing mechanistic evidence for stable barrier formation. Vitamin D gel reduced OM severity and pain in randomized trials and is suitable for use in combination with conventional treatment[113]. Moreover, autologous platelet-rich fibrin (PRF) gel releases multiple growth factors, promotes mucosal regeneration, and has low immunogenicity, making it a promising biologic option[114].

Functional inorganic NPs such as gold and silver NPs, after appropriate surface functionalization, can enhance biocompatibility and anti-inflammatory activity and may synergize with polysaccharides or antioxidant molecules to accelerate ulcer closure and reduce secondary infection, but most evidence is still from in vitro and animal studies[115, 116]. Furthermore, tetrahedral DNA nanostructures loaded with curcumin (Cur-TFNAS) combine efficient cellular entry of nucleic acid with curcumin’s anti-inflammatory properties. Binding curcumin to the nucleic acid scaffold can improve stability and maintain colloidal and serum stability at the nanoscale. Compared with free curcumin, the system shows slower and more sustained release and markedly higher cellular uptake. In models of oral mucosal injury, it showed anti-inflammatory and tissue-protective effects, supporting its use as a potentially safe carrier platform for OM prevention and treatment[117].

In summary, delivery systems for RIOM or CIOM may work mainly because improved mucoadhesion and film formation, in situ gelation, and sustained release can extend the local exposure time of antioxidant and anti-inflammatory components. This better matches the disease course driven by ROS and DNA damage, inflammation amplification, barrier breakdown, and re-epithelialization. Still, nanoformulation is not always superior to conventional topical products, suggesting that any delivery advantage likely depends on the clinical setting and dose design.

Oral mucosal trauma caused by dental surgery

In dental surgical restoration, local drug delivery systems are emerging as an important tool for tissue regeneration because they enable precise, controllable, and continuous delivery(Fig. 3A). A bilayer polyurethane patch was designed with an inner, interconnected 3D porous scaffold layer that shows strong water uptake and swelling. The scaffold surface was modified with polydopamine (PDA) to load epidermal growth factor (EGF), aiming to improve local availability and enable sustained release to support reconstruction of mucosal defects. The outer layer is a dense barrier containing AgNPs, intended to provide antibacterial activity with acceptable biocompatibility, thereby limiting bacterial invasion in the oral environment. In vitro tests showed enhanced proliferation and migration of epithelial cells and fibroblasts, and in a rabbit buccal mucosal full-thickness defect model the patch accelerated healing and improved the local inflammatory milieu[118] (Fig. 3D).AgNPs not only reduce infection risk through antibacterial activity, but may also modulate pro-healing pathways such as TGF-β/VEGF signaling to support angiogenesis and collagen deposition, accelerating granulation tissue formation and wound closure[119]. CS-based dressings, leveraging intrinsic hemostasis and mucoadhesion, provide local anti-inflammatory and antibacterial effects and can reduce postoperative oral pain and discomfort[120]. A silk fibroin scaffold composed of nanofibers was treated with 75% ethanol to induce a more stable β-sheet-rich structure and improve water stability; it also showed favorable tensile properties. The scaffold was trimmed into a membrane, placed over the wound, and fixed with sutures. No postoperative infection was noted. Overall healing was comparable to commercial acellular dermal matrix (ADM), but the silk fibroin membrane better limited wound contraction and reduced local inflammatory responses, suggesting a lower tendency toward scar formation. This provides a stable support for barrier reconstruction and continued repair in oral mucosal defects[121].

In summary, advanced local delivery systems not only outperform traditional treatments in sustained exposure and wound protection, but also provide synergistic benefits in tissue regeneration, microenvironment modulation, and prevention of complications, offering a promising option for post-operative oral wound repair.

Non treatment-related mucosal injury

Infectious oral mucosal injury

Oral infectious diseases are driven by pathogen invasion, immune dysregulation, and microenvironmental dysbiosis. For example, Candida albicans initiates fungal mucositis or candidiasis through adhesion, hyphal transition, biofilm formation, and epithelial invasion, whereas pathogens such as Porphyromonas gingivalis exacerbate host inflammation and contribute to connective-tissue and alveolar bone destruction[122]. Conventional cleaning and antibacterial and antifungal therapy have limitations, including short mucosal residence, high recurrence, variable adherence, and suboptimal efficacy, particularly in immunocompromised populations. Accordingly, there is a need to develop local, sustained, and controllable delivery strategies.(Fig. 4A).

Fig. 4.

Drug Delivery Systems for infectious oral mucosal injury and ulcerative mucosal injury. Main biomaterials-based drug delivery systems and their mechanisms of action in infectious oral mucosal injury and recurrent aphthous stomatitis. The potential of polymersome therapy for periodontal infections. (ⅰ) Schematic diagram of experimental design and treatment process. (ⅱ) Microscopic photographs and scanning electron microscopy images of fuchsin stained bacterial plaques. (ⅲ) Digital photos of bacterial colony forming units and quantitative results[136]. (ⅰ) Schematic diagram of experimental design and treatment process. (ⅱ) Inhibition zone against C. albicans, C. krusei, C. lusitaniae, and C. tropicalis[137].(ⅰ) Schematic diagram of design. (ⅱ) Photos of rat oral ulcers and calculation of ulcer area. (ⅲ) H&E staining of oral ulcer tissues and expression levels of IL-2 and IL-6[168]. Reprinted with permission from Refs [136, 137, 168]

SLNs and NLCs use blended lipid matrices to achieve high encapsulation and sustained release. SLNs can enhance mucosal retention and penetration of poorly soluble agents and improve antibacterial and antifungal activity, Cur-SLN was reported to achieve an encapsulation efficiency of 96.4 ± 0.3%, with 61.05% cumulative release within 5 h. In a buccal mucosa rinsing assay, the retention increased to 15.9% and 22%, and the MIC against C. albicans lower than that of free curcumin[123]. NLCs loaded with fluconazole or miconazole showed stronger antifungal inhibition and lower recurrence in Candida models than conventional formulations[124, 125]. Elkomy et al. developed fluconazole nanostructured lipid carriers (FLZ-NLCs) and a chitosan-coated version (FLZ-CTS-NLCs). The formulations were reported to have a mean size of ~ 335 nm and an encapsulation efficiency of ~ 73.1%, with sustained release and only mild histologic changes in rabbit oral mucosa. In vitro, the nanoformulations showed more persistent inhibition of C. albicans than fluconazole solution; chitosan coating further increased mucoadhesion and antifungal performance, and time-kill testing suggested faster fungal clearance and reduced regrowth[124]. Similarly, Clotrimazole-NLC combined with a hydrogel have been reported to improve formulation stability and antifungal performance compared with conventional preparations[126]. In addition, nystatin nanoemulsions prepared by high-energy emulsification have been described as having uniform droplet size and good stability, with lower MICs than free nystatin in vitro, suggesting that antifungal activity can be achieved at lower concentrations[127].

For polymer-based systems, Antifungal agents were individually formulated in PLA, PLGA, and alginate, Across these nanoformulations, particle size was reported to be ~ 300–900 nm, surfaces were often negatively charged, and encapsulation efficiency was typically > 70%. In pull-off testing, the maximum detachment force reached 290 ± 21 g and even 474 ± 18 g in some formulations, consistent with strong mucoadhesion. After 40 min of simulated saliva washing, drug retention increased to ~ 10–27%, whereas free drug remained at ~ 4%, supporting use in oral dosing scenarios where longer local residence is needed[128]. A CS-alginate polyelectrolyte membrane loaded with clindamycin phosphate provides sustained release and strong adhesion, suitable for local periodontal administration[129]. Another, nanoparticles prepared by spontaneous emulsification with an EUDRAGIT® RS core and a chitosan shell showed good dispersion. By giving the particles a positive surface charge, electrostatic interaction with mucin can be strengthened, and ex vivo diffusion results favored local retention rather than deep penetration. The formulation showed clear antifungal activity in vitro, with inhibition detectable early and maintained over time, supporting its use as a local oral candidiasis strategy with some durability[130]. Natural actives, including glycyrrhiza glabra L, punica granatum peel extract (PGE) after nanoformulation can gain controlled release and better compatibility, enhancing anti-infective efficacy[131, 132]. Witt et al. reported a drug-free sulfated dPG-PCL polymer with small particle size and a strongly negative zeta potential. In ex vivo oral mucosa, it entered the tissue within seconds and distributed deeper over time; saliva pretreatment increased adhesion. Functionally, it reduced IL-8 transcription and suppressed IL-8 secretion at relatively low concentrations, consistent with anti-inflammatory activity in vitro[133]. Moreover, micelles efficiently encapsulate itraconazole and amphotericin B via hydrophobic cores, thereby enhancing drug antibacterial activity while reducing cell toxicity[134, 135]. Xi et al. prepared dual-corona polyglycerol-PCL vesicles by solvent displacement. The hydrated diameter was about 310 nm; the vesicles were hollow with a reported membrane thickness of 10.6 ± 0.3 nm. They loaded the hydrophilic antibiotic ciprofloxacin and reduced the antibiotic dose required for biofilm removal by about half, suggesting improved delivery into biofilms. The authors proposed that the effect may relate to enhanced penetration and intrinsic antibacterial features of the corona design[136] (Fig. 4B).

Gel, microneedle, and metal-based delivery systems likewise show robust antibacterial and anti-inflammatory performance, with higher targeting and sustained effects. An oral spray in situ gelling system co-loading fluconazole and ibuprofen was reported to have a viscosity of 350.86 ± 1.64 cP and surface tension of 43.12 ± 0.48 N·m⁻¹ at 25 °C, with acceptable contact and spray angles. These properties support sprayability and spreading, which may help local coverage and retention. In vitro, it inhibited multiple Candida strains and showed an anti-inflammatory-related effect in a protein denaturation assay, aligning with the need for rapid coating, gelation, and prolonged exposure in the oropharyngeal region[137] (Fig. 4C). Chlorhexidine-loaded gels can act as a local drug reservoir. By changing polymer type and network structure, the release rate and duration can be tuned. In many formulations, transmucosal permeation remains low, while sustained delivery into periodontal pockets has been associated with reduced bacterial burden[138]. A hyaluronic-acid dissolving microneedle system storing minocycline was reported to retain ~ 94.4% drug content during storage and show an ex vivo insertion success rate of ~ 94.7%, supporting handling reliability. It delivered minocycline to gingiva or deep periodontal pockets, increasing intragingival drug concentration by ~ 6.1-fold and reducing systemic exposure[139]. Mesoporous silica nanoparticles (MSNs) are inorganic systems that can carry positive surface charge depending on surface chemistry. In mucosal settings, cationic surfaces may interact electrostatically with negatively charged mucus and cell membranes, which can increase local interaction and cellular uptake; particulate surface layers have also been explored as physical barriers in anti-adhesion strategies[140].

Furthermore, electrospun fibers and CMS carriers expand the delivery toolkit. Lysozyme mucoadhesive patches retain enzymatic activity, show stable residence and rapid release, and inhibit local pathogens, this study reported an encapsulation efficiency of ~ 75% while maintaining ~ 100% enzyme activity. Release reached 50.3%within 5 min and 100% by 30 min, enabling rapid protein delivery and early antimicrobial effect against local pathogens[141]. PVA-CS composite fibers loaded with α-mangostin maintain controlled release and antibacterial activity in humid conditions, supporting oral care and caries prevention[142]. Cetylpyridinium chloride (CPC) incorporated into electrospun polymer fibers (PVP/PMMA) leverages anti-biofilm activity and sustained release to inhibit Candida albicans and its biofilms[143]. PVP-HP-β-CD fibers can improve the dissolution and stability of plant bioactives. Because electrospun fibers are highly porous, release of the active compounds can be faster and more complete, which may help maintain local antioxidant, anti-inflammatory, antimicrobial activity. Such fibrous systems can also be engineered with enough mechanical integrity for placement near periodontal pockets, making them a plausible local delivery option for periodontitis therapy[144]. Ester CMS nanocarriers use layered hydrophilic/hydrophobic domains to increase the apparent bioavailability of dexamethasone. In less keratinized mucosa, CMS carriers may reach useful penetration depth even after short application times, and biocompatibility has been reported as acceptable in topical settings[92]. In addition, vermiculite-chlorhexidine nanocomposites can achieve high loading and controlled release through ion exchange and physical adsorption. MIC testing showed strong activity against S. aureus, whereas P. aeruginosa was more tolerant and inhibition depended on higher loading and longer exposure, supporting the view that sustained broad-spectrum activity varies by organism and conditions[145].

In summary, these delivery systems address limitations of conventional formulations, improving efficacy and reducing recurrence in localized infection control, inflammation management, and tissue repair, and they may offer efficient, durable, and user-friendly treatment strategies for immunocompromised patients and complex lesions (Table 3).

Table 3.

Biomaterials-Based Drug Delivery Systems for Infectious Oral Mucosal Injury

Type	Representative	Features	Applications	Advantages	Ref
SLN	Curcumin-SLN	Lipid matrix; high encapsulation	Antibacterial; anti-inflammatory	Prolonged retention and penetration; enhanced antibacterial activity	[123]
NLC	Fluconazole-NLC; Miconazole-NLC; Clotrimazole-NLC	Lipid blending; enhanced adhesion	Antifungal; controlled release	High loading; good adhesion; sustained release; stronger inhibition and lower recurrence	[124]-[126]
Nanoemulsion	Nystatin-nanoemulsion	Uniform size; stable structure	Forming a high local drug reservoir and antifungal activity	Stable preparation; fast onset	[127]
Polymer NPs	Nystatin-CS/PLA/PLGA/alginate; Clindamycin-CS-alginate; Fluconazole-EUD-CS; Glycyrrhiza-PLA/PLGA/alginate; PGE-PDNPs	Strong mucoadhesion; controlled release; higher local concentration and longer residence; tunable into adhesive gels or films	Antibacterial, anti-inflammatory; local controlled and sustained release	Longer action; fewer doses; higher local bioavailability and efficacy	[128]-[132]
Dendritic degradable polymer	dPGS-PCL	Biodegradable; strong adhesion and penetration; biocompatible	Down-regulates IL-8; local anti-inflammatory	Drug-free; anti-inflammation	[133]
Micelles	ITZ-micelles; Amphotericin B-micelles	Self-assembled hydrophilic shell–hydrophobic core	Improve solubility and tissue penetration; triggerable release	Higher solubility and penetration; responsive release	[134]-[135]
Polymersomes	PEO-b-PCL	Intrinsic antibacterial and biofilm penetration	Anti-biofilm; anti-periodontal infection	Penetrate biofilms; efficient local clearance	[136]
In situ gel	Fluconazole-Ibuprofen -gel	In-mouth gelation; strong adhesion	Antifungal with anti-inflammatory synergy	Prolonged retention; dual-action therapy	[137]
Mucoadhesive gel	CHX-gel	Strong mucoadhesion; tunable release	Local antimicrobial and disinfection; periodontal therapy and maintenance	Extended release, higher exposure, less systemic absorption; easy to prepare and use	[138]
Dissolving microneedles	Minocycline-HA MNs	Dissolve upon insertion; reach gingiva or periodontal pockets	Local antibacterial effect	Deep targeting; less systemic exposure; fewer doses	[139]
Metal-based NPs	MSNs	High surface area; tunable pores	Physical “nanocoating-like barrier” to block pathogen adhesion	Prevent adhesion and invasion; non-toxic; long-term protection potential	[140]
Electrospun nanofibers	Lysozyme-fibers; α-mangostin -CS-SH-PVA; CPC-PVP/PMMA; Polydatin/resveratrol-PVP/HPβCD	High surface area; porous network; better solubility and stability; stable release in moist environment	Antibacterial, antifungal, antioxidant, anti-inflammatory; local analgesia; pro-healing; oral care and anti-caries	Strong adhesion; stable retention; sustained release; site-specific action; stimuli-responsive control	[141]-[144]
CMS carriers	Dexamethasone-CMS	Multilayer programmable release; good permeability	Anti-inflammatory; local delivery	Higher bioavailability; precise control; improved tissue penetration	[92]
Clay-based nanomaterials	CHX-organovermiculites	Drug loading via ion exchange and physical adsorption	Broad-spectrum antibacterial; anti-biofilm	Higher loading; controlled release; durable inhibition; good stability	[145]

Ulcerative oral mucosal injury

Most oral mucosal ulcers are RAS. They are commonly seen in non-keratinized areas such as the labial mucosa, ventral tongue, and buccal mucosa, and are often accompanied by pain and burning. Some patients may also have low-grade fever, regional lymphadenopathy, and fatigue. Conventional topical analgesic, anti-inflammatory, and antimicrobial measures are mainly aimed at relieving symptoms and are limited by short mucosal residence in the humid oral cavity, high system exposure and recurrence rates, making it difficult to meet the needs of chronic recurrence management(Table 4).

Table 4.

Biomaterials-Based Drug Delivery Systems for Recurrent Aphthous Stomatitis (RAS)

Type	Representative	Features	Applications	Advantages	Ref
SLN	Cyclosporin A-SLN	Higher solubility; improved bioavailability	Pain relief; smaller ulcers; faster healing	Prolonged residence; higher local concentration	[170]
Polymer NPs	BMV-CS-PVP	High adhesion; film/patch forming	Rapid analgesia and healing	Longer action; fewer doses; higher local bioavailability	[149]
Polymer bilayer film	Prednisolone-alginate-gellan	Good water uptake, mucoadhesion, and mechanics	Anti-inflammatory; pro-healing	Shorter course; avoid systemic toxicity; easy handling	[150]
Gels	ChAlg/α-M HF; Ginger-based mucoadhesive gel; Carbomer gel; HA gel	Strong adhesion; sustained release	Analgesic; anti-inflammatory; pro-healing; shorter treatment time	Better local residence; sustained delivery; convenient use	[152]-[156]
Nanofibers	PFE-CS-Gel; DXM-DYC-nanofibers	High adhesion, hydrophilicity, and biocompatibility; controlled release	Analgesic; antibacterial; antioxidant; pro-healing	Better residence; longer duration	[166, 168]
Mucoadhesive pastes	DS-bFGF; Amlexanox-paste; licorice extract-paste	Strong adhesion	Effective analgesia; reduced severity; faster healing	Easy clinical use; good safety and adherence	[172]-[174]

Polymer-based delivery systems, owing to strong mucoadhesion and controlled-release performance, can maintain stable drug exposure at the lesion and reduce dosing frequency. Hu et al. used a mussel-inspired strategy to introduce catechol groups onto a buccal adhesive film and combined it with nanoparticles to improve mucosal residence and sustained release. The system showed stronger adhesion on wet tissue and better resistance to wash-off. It also increased drug transport across the mucosal barrier, helping maintain higher local drug levels, and the reported relative bioavailability was higher than direct oral administration[146]. Polyglutamic acid and tannic acid composite nanoparticles loaded with doxycycline and remain well dispersed in water. In simulated saliva, they showed a slower release profile. Fluorescence-based retention testing in a rat oral-ulcer model suggested markedly higher retention at the ulcer site. Based on these properties, the platform was discussed for combined control of local infection and inflammation, with staged intervention across healing phases[147]. A hydroxypropyl methylcellulose monolayer mucoadhesive film co-loaded with ornidazole and dexamethasone achieves concurrent antibacterial and anti-inflammatory therapy[148]. A Chitosan/pvp-based composite film developed by Sizílio et al. delivered betamethasone-17-valerate (BMV), providing rapid analgesia and faster healing[149]. Furthermore, a bilayer membrane designed by Farid et al. could absorb water and swell, forming a gel-like diffusion layer and maintaining adhesion for longer residence in a moist oral environment. In vivo measurements reported residence times of 130.33 ± 11.17 min on gingiva and 66.83 ± 19.65 min on buccal mucosa, with sustained release of prednisolone sodium phosphate, which may help reduce systemic exposure[150].

Gel systems combine controlled release, barrier protection, and pro-repair functions. A adhesive hydrogel patches (AHPs) that gradually releases a tridentate complex of protocatechualdehyde-Fe³⁺ achieves anti-inflammation, granulation, and re-epithelialization in sequence[151]. An α-M hydrogel film based chitosan-alginate (ChAlg/α-M HF) was prepared by a solvent evaporation method. In the composite network, α-M showed more uniform dispersion with reduced crystallinity, which supported a stable drug-loaded film and may favor local retention at the lesion site. The film showed an initial burst release within the first 2 h, which may help achieve earlier local exposure. The film also had a high swelling capacity, which can increase the contact area with the mucosa. A mucoadhesive time of 46.7 min on fresh mouse mucosa was reported, suggesting that the film can remain in place long enough to support local coverage under salivary washout and mechanical disturbance[152]. A randomized controlled study suggested that although an antioxidant-containing gel did not markedly accelerate healing, it reduced pain more quickly and showed good safety[153]. In addition, some matrices themselves have therapeutic effects. Carbomer-based mucoadhesive gels, with or without aloe, isolate irritants and dampen inflammation, relieving mild RAS pain and shortening disease course[154]. By virtue of long-term hydration, support for cell migration, and ECM remodeling, HA gels have reduced pain and accelerated healing in multiple clinical studies, outperforming triamcinolone acetonide[155, 156]. A thermosensitive in situ gel designed by Gurav et al. co-loads multiple drugs, synergizes analgesic and antimicrobial actions, and reduces dosing frequency[157].

Dissolvable MNs combine barrier penetration with localized controlled release, enabling precise delivery to deeper mucosa and on-demand dosing. For example, a silk fibroin dissolving microneedles load LPS-pretreated BMSC-derived exosomes in the needle tips, with zeolitic imidazolate framework-8 (ZIF-8) placed in the base layer. The needles degrade in body fluids within about 15 min, while the exosomes can be continuously released in vitro for more than 7 days. This enables rapid delivery in the dynamic oral environment through mechanical penetration first, followed by long-term release to maintain bioactivity, reduce infection-related inflammation, and promote ulcer healing[158]. Similarly, betamethasone microneedles prepared by ultrasonic casting release betamethasone to the ulcer base within 3 min after insertion into the mucosa, providing rapid local anti-inflammatory and analgesic effects[159]. Multifunctional HA-microneedles can co-deliver anti-inflammatory, reparative, and antibacterial cues, improving the ulcer microenvironment and accelerating healing[160] Keratin–hyaluronic acid microneedles loaded with hop extract (KMNs@HE) can also modulate immunity and promote regeneration[161]. Through bilayer, core–shell structure, and stimuli-responsive designs, microneedles enable staged or sequential release. Meng et al. designed double-layer sequential dissolving MNs which a fast-dissolving HA layer provides rapid analgesia, while a crosslinked hyaluronic acid methacryloyl (HAMA) outer layer delivers sustained anti-inflammatory and reparative effects. This sequential-release system limits repeat injections, improves adherence, and matches the therapeutic sequence of pain relief, inflammation control, and tissue repair for multistage management of oral mucosal disease[162]. Similarly, core–shell microneedles loaded with multiple drugs reported by Yu et al. provide rapid analgesia via the outer layer and persistent anti-inflammatory and reparative effects via the inner core, covering the full treatment cycle[163]. Moreover, ROS-responsive hydrogel MNs become “activated” at ulcerative inflammatory sites, exerting antioxidant, antibacterial, anti-inflammatory, and pro-epithelial-healingeffects that specifically address local oxidative stress and infection risk[164].

Electrospun nanofibers extend local effects and protect labile agents through their high surface area and porosity. Double-layered CS polymer nanofiber sheets loaded with human growth hormoner (hGH) promote oral wound healing[165]. Thiolated CS-gelatin (Gel) fibers carrying pomegranate flower extract (PFE) show antioxidant and antibacterial activity and enhance tissue regeneration[166], while poly(l-lactic acid) (PLLA)-based nanofiber networks loaded with high-dose curcumin or combined with dyclonine hydrochloride exhibit good mucoadhesion and synergistic anti-inflammatory, antibacterial, and analgesic effects[167]. A film network was constructed from carboxymethylated cellulose nanofibers (CNF) and alginate (Alg). It provided mechanical support and wet-tissue adhesion, and it was reported to maintain structural integrity in water for up to 14 days, which may help sustain adhesion and stable coverage in the moist oral environment. Importantly, it enabled rapid release of dexamethasone (about 60% released within 20 min) and sustained release of dyclonine (about 75% released within 6 h), and it accelerated ulcer healing and relieved pain in animal models[168] (Fig. 4D). Polyacrylate-based nanofibers loaded with ketoprofen also show anti-inflammatory activity and reduced the clinical severity of mucositis[169]. Other systems have favorable effects. Cyclosporine A encapsulated in SLN combined with an adhesive gel prolongs residence, raises local concentrations, and supports both healing and analgesia[170]. A curcumin-loaded collagen scaffold combined with adipose-derived stem cells (ADSCs) used naturally strong collagen fibers as a porous framework and incorporated an anti-inflammatory molecule, achieving local inflammation downregulation and oxidative stress improvement. Simultaneously utilizing stem cells to promote tissue regeneration, achieving dual anti-inflammatory and regenerative effects in animal experiments[171]. In addition, mucoadhesive pastes containing basic fibroblast growth factor (bFGF) and diosmectite (DS) provide anti-inflammatory and reparative benefits, shorten healing time, and improve pain in clinical trials[172]. Pastes containing amlexanox or licorice extract also relieve pain, promote healing, and show good safety[173, 174].

Oral cancer

Oral squamous cell carcinoma (OSCC) is a multifactorial, multistep disease that often arises from potentially malignant disorders such as leukoplakia and erythroplakia. It involves dysregulated p53, PI3K/AKT, and EGFR signaling, together with immune-microenvironment imbalance, and shows field cancerization, predisposing to multifocal lesions and recurrence [175]. Early symptoms are often subtle; as disease progresses, non-healing ulcers, bleeding, trismus, and cervical lymphadenopathy may appear. Conventional management centers on surgery combined with chemoradiotherapy. Nevertheless, high recurrence rates, functional impairment, and treatment-related toxicities persist, underscoring the need for precise diagnosis and novel local or systemic delivery strategies (Table 5) (Fig. 5A).

Table 5.

Biomaterials-Based Drug Delivery Systems for Oral Cancer

Type	Representative	Features	Applications	Advantages	Ref
SLN	Curcumin-SLN	High biocompatibility; sustained release	Promote healing; suppress epithelial dysplasia; improve mucosal structure; pain relief	Greater stability and penetration; sustained release; lower dose	[176]
Liposomal carriers	Curcumin liposome; Gen-lipid nanocarrier; Doxorubicin-liposome	High loading; strong adhesion; controlled release	Local antitumor activity	Longer local action; lower systemic toxicity; strong in-vitro antitumor effect	[177]-[179]
Polymer NPs	Oxaliplatin-CS; Curcumin-CS; DOX-CS-HA; Cisplatin-CS; miRNA-CS; Imperata cylindrica extract-PEG	High adhesion; film/patch forming; surface modification for uptake; improved stability and protection from degradation	Local antitumor activity	Longer duration; fewer doses; higher local bioavailability and efficacy	[180]-[185]
Polymer matrix films	5-FU-acrylic-methacrylic copolymers	Polymer matrix for stronger adhesion; tunable release; deep penetration	Very low-dose sustained exposure for tumor control	Avoid systemic toxicity; high local concentration; low dosing frequency	[186]
Micelles	Cisplatin-micelles (NC-6004)	Self-assembled hydrophilic shell–hydrophobic core; efficient loading of poorly soluble drugs	Local delivery of antitumor agents	Lower free-drug toxicity; better intratumoral penetration	[187]
In situ gel	EGCG-gel spray	In-mouth gelation; strong adhesion	Inhibits early progression of oral mucosal fibrosis	Higher stability; prolonged residence; convenient use	[188]
Mucoadhesive gel	Dexamethasone-gel	Strong mucoadhesion; sustained release	In vivo inhibition of inflammation and collagen deposition; improved elasticity in oral fibrosis models	Better localization at absorption site; prolonged delivery	[189]
Dissolving microneedles	Photosensitizers (Aza-BODIPY, Indocyanine green)	Precise deep mucosal delivery; no sharps waste after dissolution	Combination therapy	Precise localization; selective tumor killing; minimal collateral damage	[190]-[191]
Nanobead- loaded microneedles	Triamcinolone-silk fibroin MNs	“Depot” for gradual release	Local anti-inflammatory and anti-fibrotic effects	Markedly prolonged action; fewer administrations	[192]
Metal NPs	AsNPs; Cetuximab/Cisplatin-AuNPs	Unique physicochemical properties trigger programmed death; radiosensitization/chemosensitization	Induce anoikis; inhibit adhesion and migration; enhance EGFR blockade; suppress proliferation and invasion; radio-/chemo-sensitization	Direct antitumor and anti-metastatic potential; combination therapy; reduced required dose; manageable toxicity	[193]-[197]

Fig. 5.

Drug Delivery Systems for treatment of oral cancer and diabetes related oral mucosa injury. Main biomaterials-based drug delivery systems and their mechanisms of action in oral cancer and diabetes related oral mucosa injury. (ⅰ) Schematic diagram of design. and representative in vivo NIR fluorescence images of AZP10 distribution. (ⅱ) the change in tumor volume with time[191]. (ⅰ) A flow diagram illustrates the experimental setup.(ⅱ) Representative images of mucosal healing, the progression of mucosal healing, and wound healing efficiency of oral ulcers[202]. Reprinted with permission from Refs [191, 202]

Lipid-based carriers are improving local OSCC therapy. SLNs enhance curcumin stability, mucosal permeation, and sustained release, and short-term clinical data suggest lesion improvement, reduced dysplasia, and pain relief[176]. In another study, lipid-core nanocapsules combined with a chitosan-based thermosensitive gel had a mean size of about 218–224 nm with a narrow size distribution. The zeta potential shifted from negative to positive after coating, and the encapsulation efficiency was close to 100%. As an oral delivery system, it gelled in situ at oral temperature to improve local residence and reduce salivary washout. Importantly, the system provided curcumin with some transmucosal delivery while showing a sustained-release profile and acceptable biosafety, and it showed antitumor activity in vitro[177]. A chitosan-modified lipid nanocarrier loaded with the proapoptotic lipophilic drug genistein (Gen) improves mucoadhesion and controlled release, reducing salivary wash-off. It has the potential to serve as a maintenance therapy for oral cancer patients[178]. In addition, a liposomes patch was prepared by an ethanol injection method. Lyophilized, reconstitutable liposomes were used to support formulation stability, and the composition and patch structure were optimized to improve resistance to salivary washout. The liposomes also reduced rapid doxorubicin leakage and enabled prolonged release (< 15% over 24 h), with the aim of maintaining local drug levels and limiting systemic exposure. In animal studies, this approach was associated with tumor growth inhibition and low systemic adverse effects[179].

In polymer-based drug delivery system, CS or with HA forms high-adhesion NPs to load oxaliplatin, DOX, cisplatin, or curcumin, achieving prolonged mucosal residence and selective uptake, reducing intravenous toxicity. For example, tripolyphosphate (TPP) can ionically crosslink chitosan to form drug-loaded nanoparticles, achieving an oxaliplatin encapsulation efficiency (EE) of 89.1 ± 4.7% and a drug loading (DL) of 44.5 ± 2.4%, with acceptable physicochemical stability. Catechol-modified chitosan may further increase nanoparticle residence on the mucosal surface. In artificial saliva, doxorubicin showed a gradual release profile and improved efficiency against tumor cells. These systems have been reported to show antitumor effects in animal models and clinical studies[180–183]. Similarly, chitosan nanoparticles prepared by TPP-mediated ionic gelation were used to deliver anti-fibrotic miRNA. The nanoparticles were in the submicron range and carried a positive surface charge, which can help limit aggregation and support cellular uptake. A cationic surface may also facilitate lysosomal escape, reducing intracellular inactivation of nucleic acids. Delivery of anti-fibrotic miRNA using chitosan nanoparticles downregulated TGFB1, ACTA2, and other fibrosis-related genes, suggesting potential for oral submucous fibrosis (OSF). Given the wet oral environment and salivary washout, intralesional injection was proposed to improve local contact and delivery, thereby limiting systemic exposure and related immune concerns[184]. Mucoadhesive films from degradable polymers can build persistent drug layers. PEG-based systems loading Usnea barbata (L.) dry acetone extract (F-UBA) botanical extracts improve stability, slow degradation, and enhance antitumor effects of drug [185]. Embedding 5-FU in adhesive polymers allows deeper penetration and low-dose continuous exposure, reducing systemic toxicity and supporting local chemotherapy tablets for oral tumors[186]. In addition, researchers have used micelles to efficiently load cisplatin-the key chemotherapeutic for head and neck squamous cell carcinoma-thereby markedly improving intratumoral penetration, enhancing antitumor activity, and reducing the toxicity of the free drug[187].

For gels and microneedles system, nanocubospray or mucoadhesive gels can form films in situ, enhancing the stability and mucoadhesion of epigallocatechin 3-gallate (EGCG) or dexamethasone sodium phosphate, effectively suppressing inflammation, reducing collagen deposition, and improving tissue elasticity, and make them suitable for premalignant conditions[188, 189]. Dissolving microneedles deliver photosensitizers deep into mucosa for photothermal or photodynamic therapy, enabling selective tumor killing[190, 191]. Kothari et al. fabricated PVA/PVP microneedles by micromolding to load the photosensitizer AZP10. The microneedles maintained mechanical strength, dissolved within about 5 min after insertion into oral mucosa, and released ~ 96% of AZP10 within 10 min, with improved transmucosal delivery. In monolayer cells and 3D tumor spheroids, AZP10 showed a PDT antitumor effect after irradiation, with a cell death rate of 95 ± 5%, accompanied by increased ROS and reduced mitochondrial membrane potential[191] (Fig. 5B). Moreover, a mucoadhesive silk fibroin (SF) microneedle patch act as a sustained-release depot for triamcinolone acetonide to treat oral mucosal fibrosis, meeting the need for continuous clinical dosing[192].

Metal NPs support targeted delivery and synergistic sensitization. Covarrubias et al. found that AsNPs can induce apoptosis, inhibit adhesion and migration, and show direct antitumor effects[193]. AuNPs conjugated with cetuximab or cisplatin enhance EGFR blockade, impair proliferation and invasion, and act as radio/chemo-sensitizers, potentially lowering dose requirements[194–196]. Overall, these strategies provide sustained exposure via mucoadhesion, deep delivery, and controlled release in a saliva-rich, high-clearance environment, while reshaping immunity and the tumor microenvironment to curb recurrence and systemic toxicity, offering translatable routes to precise local or systemic combination therapy for OSCC.

Diabetes related oral mucosa injury

Diabetes-related oral mucosal injury is a cascade driven by metabolic dysregulation that leads to microcirculation dysfunction, chronic inflammation, and impaired repair. Hyperglycemia results in reduced microvascular perfusion and immune dysregulation, causing hypoxia and down-regulation of growth factors. Concomitantly, excess ROS and AGEs up-regulate MMPs, degrade extracellular matrix, and intensify cellular stress, ultimately delaying re-epithelialization and tissue remodeling. Conventional local care is limited by the oral environment, with short residence, variable adherence, and poor treatment continuity. In diabetes, persistent inflammation together with ischemia and hypoxia is particularly difficult to reverse(Fig. 5A).

Emerging delivery systems enhance therapeutic efficacy through strong mucoadhesion and multi-target synergy. For example, the GOx-CAT nanogel (GCN) constructed by Zheng et al. consumes glucose, scavenges ROS, improves local oxygenation, and accelerates ulcer closure via a glucose oxidase and catalase cascade[197]. Mussel-inspired adhesive hydrogels maintain robust adhesion and antioxidant activity in the acidic, inflamed microenvironment, thereby shortening the inflammatory phase[198]. A self-healing, dual-responsive hydrogel was built on a four-arm polyethylene glycol (PEG) backbone and functionalized with dopamine and phenylboronic acid (PBA). The network responds to both glucose and ROS. Under hyperglycemic and oxidative conditions, the dynamic network is more readily remodeled, which can support lesion-site release and material renewal. In a diabetic oral mucosal wound model, it enabled glucose and ROS-responsive release of sitagliptin, with reduced inflammation-related readouts and increased repair-related phenotypes, together with improved angiogenesis and epithelial repair. The authors also noted that gelation of the PEG-DP/PEG-DPS system was slower than that of an unmodified four-arm PEG hydrogel, which may facilitate injection and filling of irregular defects and supports its feasibility for intraoral use[199].

In addition, active biomaterials and penetrating systems further improve delivery performance. Polymetallic-oxide bioactive glass nanofibres (BGnf) promote re-epithelialization and angiogenesis in diabetic models[200]. Tetrahedral DNA nanostructures (TDNs) enable efficient miR-132 delivery, enhancing fibroblast migration and neovascularization[201]. A microneedle patch was prepared by loading Mg–Zn layered hydroxide salt nanosheets functionalized with γ-polyglutamic acid and quercetin (LHSQ) into a γ-polyglutamic acid (γ-PGA) microneedle matrix. The microneedles pierce the mucosal epithelium and create conical microchannels. About 70% of LHSQ was released within 35 min, and release was faster at lower pH, suggesting a degree of acid-responsive rapid release. In vitro and in vivo, the system showed antibacterial, antioxidant, and immunomodulatory effects relevant to wound repair. In oral ulcers, where local acidity, ROS elevation, and infection risk may coexist, this patch supports puncture-assisted delivery and acid-accelerated release, with combined antibacterial, antioxidant actions and regulation of macrophage polarization to intervene in inflammation and repair[202] (Fig. 5C).

In summary, these systems enable coordinated, multi-target interventions at key pathogenic nodes of diabetic oral mucosal injury, offering substantive support and translational promise for precise, efficient, and individualized clinical management.

Challenges and outlook

The design of drug delivery systems in the oral cavity first faces two core contradictions: strong adhesion and long-term retention, as well as the ability to penetrate the mucus layer and penetrate deep into the lesion; It requires both high load and controllable release, as well as good sensory performance and scalable preparation. It is important to note that the mucus layer is not only the anchoring site for mucoadhesive systems but also a dynamic barrier. Through trapping and clearance, mucus can limit how much of a formulation reaches the epithelial surface. Therefore, stronger mucoadhesion alone may not lead to better tissue delivery. A more practical approach is to balance local residence and deep tissue access, and to build mechanisms that allow a switch between them. In recent designs, mucoadhesion is used early to improve local positioning, and then nonspecific mucin interactions are reduced to improve delivery to the target tissue. Studies have reported that, compared with mucus-adhesive nanoparticles, mucus-penetrating nanoparticles show faster diffusion in mucus and distribute more deeply within the mucus layer[203]. Based on this, a core–shell design can be considered: an outer mucoadhesive layer for initial retention and barrier formation, and an inner mucus-penetrating core optimized for mucus and tissue penetration, which may shorten the onset lag and extend tissue exposure. More integrated platforms may further combine lesion coverage, deep delivery, and stimulus-responsive release. For example, film-forming gels can act as a local drug reservoir and protective layer, while structured systems such as microneedles provide depth control and placement. Furthermore, an integrated carrier with lesion barrier, deep delivery, and on-demand release is formed through deep integration of multiple systems. Building on the stage-specific features of oral diseases, a multiresponsive system should be established to meet sequential therapeutic needs-analgesia, inflammation control, and tissue repair-thereby enabling phase-based management with rapid release during the acute inflammatory phase and sustained release during the repair phase. In addition, peptides, antibody ligands can bind to polymersomes or micelle systems to enhance cellular uptake and release precision. However, their added value should be supported by evidence from tissue distribution, cellular uptake, and efficacy endpoints. Ultimately, with acceptable sensory properties and manufacturing consistency, such systems can increase local efficacy while reducing treatment burden.

Currently, clinical translation still faces several constraints. Safety is paramount. Long-residence mucoadhesive carriers may shift oral microbiota homeostasis and raise secondary-infection risk. Oral microorganisms can adhere to non-shedding hard surfaces and to the mucosal epithelium, forming biofilms. Surface features and anatomical location can affect protein adsorption and biofilm formation, thereby shaping microbial adhesion and community balance. Although current clinical data are not fully consistent, in patients with oral mucositis after hematopoietic stem cell transplantation, the use of gel formulations was not associated with worse bacterial or fungal colonization outcomes[204]. In contrast, in a randomized trial in head and neck radiotherapy, microbiome-related indices consistent with dysbiosis were reported to change[110]. Importantly, follow-up in these studies is often limited to the treatment period or short-term observation, and long-term data on the microbiome and local immune homeostasis are limited. Separately, long-term foreign materials such as orthodontic appliances and intraoral implants have been reported to alter the oral microbiome, commonly as reduced community diversity, increases in caries-associated taxa, and shifts in the proportion of potentially pathogenic taxa[205]. Therefore, when a material is intended to remain in the oral cavity and changes the local surface microenvironment, potential effects on microbiome homeostasis should be evaluated systematically, using colonization and microbiome endpoints. In recent years, more microbiology evidence in oral mucositis has suggested that anticancer therapy is accompanied by community changes, and some microbial patterns are associated with mucositis severity, supporting inclusion of microbiome outcomes in evaluation frameworks. Metal-containing composites can undergo ion dissolution and particle migration in saliva or inflamed microenvironments, causing local accumulation, gastrointestinal exposure after swallowing, and uncertain distal distribution. In the oral cavity, mechanical wear and corrosion of implants and metal-containing materials can release particles and ions. Oliveira and colleagues reported findings consistent with osteoclast activation, the presence of macrophages containing metal microparticles, and signals related to genotoxicity in the presence of metal particles and ions, suggesting that implant-derived debris may have cytotoxic and genotoxic potential in peri-implant tissues[206]. Bressan and colleagues also discussed that metal particles can increase ROS levels, recruit neutrophils, and increase metalloproteinase activity, which may affect the balance between cell survival and tissue remodeling during bone regeneration[207]. In addition, metal particles may alter biofilm composition and induce DNA-damage signaling in oral epithelial cells, which can weaken the epithelial barrier and worsen local inflammation; inflammation may further promote corrosion and particle release, forming an unfavorable cycle[208]. Animal studies have also detected systemic accumulation after exposure to implant-related metal debris, supporting the possibility of distribution beyond the local site[209]. However, most evidence is from in vitro and animal studies, so oral delivery applications still require careful evaluation based on dose, exposure route, and duration.

Evidence on long-term, low-dose exposure and immune homeostasis remains limited. Evidence on long-term effects on immune homeostasis under chronic, low-dose exposure remains limited. For example, clinical studies of Ag-containing oral gels have generally reported acceptable tolerability during treatment, without clear signals of severe adverse events, but follow-up is usually short and does not address repeated use or chronic exposure. It is also worth noting that, although exposure contexts differ, oral exposure studies have suggested that low-dose oral titanium exposure may disrupt intestinal and systemic immune homeostasis and may be linked with preneoplastic changes[210]. These data suggest that systemic immune effects are possible, but direct evidence that topical oral formulations produce measurable systemic immune effects under real-world conditions is still limited. Finally, immune effects are not necessarily driven only by metal ions. Some surface modifications used to reduce protein adsorption and prolong circulation can also alter immune responses. For example, PEGylation refers to covalent attachment of poly(ethylene glycol) (PEG) to nanocarriers, proteins, or peptides to extend circulation half-life, but PEG immunogenicity has been widely discussed. Pre-existing anti-PEG antibodies have been reported even in individuals without prior PEGylated therapy, and PEG-related immune responses can contribute to complement activation, accelerated blood clearance (ABC), and complement activation-related pseudoallergy (CARPA), with potential safety implications[211]. Therefore, in addition to routine recording of local irritation and adverse events, future studies could also track changes in microbiome composition and markers linked to inflammation and barrier function. When relevant, anti-PEG antibodies and complement markers may be added. For metal-containing systems, it may also be necessary to quantify metal ion and particle release and in-vivo distribution, together with immune-related biomarkers. Where possible, systems that are biodegradable, have low accumulation risk, and have a low risk of metal ion leaching should be prioritized.

Manufacturing and quality control, using polymeric micelles as an example. Polymeric micelles can be prepared by conventional methods such as direct dissolution, dialysis, and thin-film hydration, as well as newer approaches including microfluidic assembly and stimuli-responsive self-assembly. These methods differ in process control, residual solvent burden, reproducibility, and feasibility for scale-up. Conventional approaches often involve organic solvents and multiple steps, and they can be sensitive to batch variables such as mixing, concentration, and temperature. In contrast, newer strategies generally aim to improve scalability, reduce or avoid organic solvents, simplify the workflow, and improve formulation consistency. Dialysis can improve micelle uniformity and help remove organic solvents, but it is time-consuming, operator-dependent, and sensitive to membrane properties, and scaling up often requires added engineering controls and process monitoring. Stimuli-responsive micelles can be designed to release drugs in response to triggers such as pH or enzymes, but this usually requires cleavable bonds or functional units, which adds synthesis and characterization steps and introduces additional quality attributes that must be controlled. Therefore, nanomedicine manufacturing can follow a quality-by-design approach, using quantitative control of critical quality attributes (CQAs)-such as particle size, PDI, drug loading, free-drug fraction, residual solvent, release profile, and stability-and linking them to critical process parameters (CPPs), including the solvent/non-solvent ratio, the mode and rate of addition and mixing, and temperature. Establishing clear CPP-CQA relationships can help maintain consistency during scale-up and support regulatory review.

Conventional treatment often emphasizes symptomatic relief after injury, while mucosal damage in populations such as radiotherapy and chemotherapy is highly predictable. Therefore, biomaterials-based drug delivery systems should support to continuous management. Before therapy, baseline mucosal status, oral hygiene, past mucosal disease, planned treatment, salivary flow, and nutrition should be assessed to stratify risk. and high-risk individuals should receive preventive medication and oral care education on adhesion barriers, antioxidant and anti-inflammatory drug delivery systems to reduce the initial inflammatory cascade. During acute pain or ulceration, combine rapid-analgesic, antibacterial, and anti-inflammatory delivery systems. As inflammation subsides and re-epithelialization begins, prioritize sustained pro-repair systems to limit scarring and fibrosis. Microneedle patches together with stimuli-responsive gels, micelles, or vesicles can provide deep localization and sequential release. Finally, tissue-engineered nanoscaffolds can support complete mucosal reconstruction and functional recovery. After wound closure, moisturizing barriers combined with antioxidant and antibacterial slow-release systems may help restore and maintain microenvironmental homeostasis.

In conclusion, based on the available evidence, bio-delivery systems tend to show benefit when they improve local residence and controlled release under oral washout by using mucoadhesion, film or gel formation, and depot-like behavior. This can help provide more stable local anti-inflammatory, antioxidant, or antimicrobial exposure during ulcer- and inflammation-dominant phases, and it may translate into improvements in pain control, inflammation measures, or healing rate. However, not all approaches outperform conventional topical formulations, so any claimed advantage needs careful and systematic validation. This review also has unavoidable limitations. Existing studies vary widely in disease types, formulation composition, dosing frequency, and endpoints, and true head-to-head comparisons are uncommon, making cross-platform ranking difficult. Patient-important outcomes, such as eating ability, weight change, secondary infection, hospitalization, or treatment interruption, are also underreported. Many studies rely on in-vitro or animal models, where salivary washout, mechanical friction, and mucus turnover are often simplified, which may bias estimates of residence and penetration. Safety data are commonly limited to the treatment period or short follow-up, leaving uncertainty about longer-term effects on the microbiome and local immune homeostasis, as well as systemic exposure under repeated use. In addition, literature reporting on manufacturing reproducibility and quality control is often incomplete, limiting assessment of scalability. Finally, publication bias and limited reporting of negative results may skew the evidence toward positive findings. Therefore, more standardized research design and transparent data reporting are needed to correct this bias.

Author contributions

Xingchen Peng and Fengming You planned the study. Jiayi Yu and Xueke Li searched literature and wrote the manuscript. Xi Fu revised the manuscript. Jinyu Wen, Yifang Jiang and Qixuan Kuang contributed to review and proofreading. Yi Sun and Ding Bai contributed to search literature and data curation. Fengming You provided critical revisions to the manuscript and funding acquisition. Chuan Zheng reviewed and supervised the manuscript. All authors commented on previous versions of the manuscript, Chuan Zheng, Fengming You and Xingchen Peng acted as guarantor.

Funding

This study has received support from Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0503000).

Data availability

Data are available upon reasonable request.

Declarations

Ethics approval

Not applicable.

Competing interests

The authors declare no competing interests.