# Advances in the treatment of recurrent aphthous stomatitis: from synthetic and natural drugs to novel drug delivery systems

**Authors:** Xiangran Kong, Lin Fan, Dawei He, Lin Wang, Jiang Sun

PMC · DOI: 10.3389/fphar.2026.1715554 · Frontiers in Pharmacology · 2026-02-13

## TL;DR

This paper reviews current and emerging treatments for recurrent mouth ulcers, focusing on natural medicines and new drug delivery systems to improve effectiveness and safety.

## Contribution

The paper integrates insights on natural drugs and novel delivery systems to propose a future research direction for RAS therapy.

## Key findings

- Natural medicines like licorice and quercetin show promise due to their multitarget mechanisms and safety.
- Novel delivery systems such as microneedles and nanomedicines improve drug retention and therapeutic efficacy.
- Combining natural drugs with advanced delivery systems is a key direction for future RAS treatment.

## Abstract

Recurrent aphthous stomatitis (RAS), the most common inflammatory disease of the oral mucosa, has a complex etiology and diverse pathogenesis. To date, no curative treatment exists. Recurrent oral ulcers severely impair patients' quality of life, making the development of highly effective and safe therapeutic strategies an urgent priority in current clinical research.

Literature references were sourced from publications retrieved via searches on GeenMedical, X-mol, CNKI, and PubMed using the search terms “recurrent aphthous stomatitis” OR “recurrent aphthous ulcer” OR “oral ulcer” AND “treatment” in English and Chinese. The focus was on two dimensions: drug types and delivery systems.

Synthetic drugs such as corticosteroids have clear efficacy, but their potential adverse reactions limit their long-term use. In contrast, natural medicinal components such as licorice and quercetin are gaining increasing attention because of their multitarget mechanisms of action, favorable safety profiles, and therapeutic effects. With respect to delivery systems, novel adhesion agents, microneedles, and nanomedicines currently in development have been evaluated. These advantages include prolonged retention time on ulcer surfaces, enhanced biosafety, improved therapeutic efficacy, and current limitations.

Natural medicines have potential as novel therapeutic options with high efficacy and safety in clinical settings. By enhancing local drug retention and amplifying therapeutic effects, novel delivery systems open new avenues for RAS therapy. Integrating the therapeutic advantages of natural medicines with the precision and sustained-release characteristics of advanced delivery systems represents a key direction for future research.

## Linked entities

- **Chemicals:** quercetin (PubChem CID 5280343)

## Full-text entities

- **Genes:** GH1 (growth hormone 1) [NCBI Gene 2688] {aka GH, GH-N, GHB5, GHN, IGHD1A, IGHD1B}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, COX8A (cytochrome c oxidase subunit 8A) [NCBI Gene 1351] {aka COX, COX8, COX8-2, COX8L, MC4DN15, VIII}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, NR3C1 (nuclear receptor subfamily 3 group C member 1) [NCBI Gene 2908] {aka GCCR, GCR, GCRST, GR, GRL}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, ALOX5 (arachidonate 5-lipoxygenase) [NCBI Gene 240] {aka 5-LO, 5-LOX, 5LPG, LOG5}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 4513] {aka COII, MTCO2}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, PTGS2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 5743] {aka COX-2, COX2, GRIPGHS, PGG/HS, PGHS-2, PHS-2}
- **Diseases:** aphthous stomatitis (MESH:D013281), erythema (MESH:D004890), periodontal diseases (MESH:D010510), thromboembolic disorders (MESH:D013923), peripheral neuropathy (MESH:D010523), allergic (MESH:D004342), oral (MESH:D020820), inflammatory drugs (MESH:D000081015), mucositis (MESH:D052016), Cytotoxicity (MESH:D064420), ulcer (MESH:D014456), oral mucositis (MESH:D013280), infections (MESH:D007239), cardiovascular diseases (MESH:D002318), lichen planus (MESH:D008010), saliva flushing (MESH:D005483), metabolic diseases (MESH:D008659), fatigue (MESH:D005221), dermatitis (MESH:D003872), hyperemia (MESH:D006940), Behcet's disease (MESH:D001528), oral diseases (MESH:D009059), edema (MESH:D004487), chronic kidney disease (MESH:D051436), anxiety (MESH:D001007), atrophy (MESH:D001284), mucosal irritation (MESH:D001523), oral lichen planus (MESH:D017676), Pain (MESH:D010146), RAS (MESH:C538145), oral mucous membrane diseases (MESH:D010390), injury (MESH:D014947), inflammation (MESH:D007249), taste disturbances (MESH:D013651), fibrosis (MESH:D005355), mouth ulcers (MESH:D019226)
- **Chemicals:** TA (MESH:D014222), flavonoid (MESH:D005419), levamisole (MESH:D007978), magnesium (MESH:D008274), CBD (MESH:D002185), cannabinoid (MESH:D002186), Amlexanox (MESH:C045742), Beta-glucans (MESH:D047071), ROS (MESH:D017382), saponins (MESH:D012503), PLGA (MESH:D000077182), luteolin (MESH:D047311), alcohol (MESH:D000438), LPS (MESH:D008070), Minocycline (MESH:D008911), Sodium Carboxymethyl Cellulose (MESH:D002266), steroid (MESH:D013256), DYC (MESH:C100063), naltrexone (MESH:D009271), amine (MESH:D000588), triterpenoid (MESH:D014315), emodin (MESH:D004642), benzydamine hydrochloride (MESH:D001591), MC (MESH:C061001), EC (MESH:C013517), dexamethasone (MESH:D003907), PVA (MESH:D011142), fluocinolone acetonide (MESH:D005446), indomethacin (MESH:D007213), BDP (MESH:C011175), penicillin (MESH:D010406), glycerol (MESH:D005990), sodium (MESH:D012964), Tetracycline (MESH:D013752), HAMA (-), hydrogen peroxide (MESH:D006861), lidocaine (MESH:D008012), Curcumin (MESH:D003474), HEC (MESH:C002283), amoxicillin (MESH:D000658), clobetasol (MESH:D002990), ethanol (MESH:D000431), aldehyde (MESH:D000447), HA (MESH:D006820), insulin (MESH:D007328), PVP (MESH:D011205), rhein (MESH:C020491), chlorhexidine (MESH:D002710), Thalidomide (MESH:D013792), CMC (MESH:C514968), BSP (MESH:C028994), Isoliquiritigenin (MESH:C040920), gibberellin (MESH:D005875), Tetracyclines (MESH:D013754), PGE2 (MESH:D015232), terpenoid (MESH:D013729), amide (MESH:D000577), acetylsalicylic acid (MESH:D001241), water (MESH:D014867), phospholipids (MESH:D010743)
- **Species:** Glycyrrhiza glabra (species) [taxon 49827], Curcuma longa (turmeric, species) [taxon 136217], Artemisia argyi (species) [taxon 259893], Peptostreptococcus (genus) [taxon 1257], Lonicera japonica (Japanese honeysuckle, species) [taxon 105884], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Polygonum aviculare (species) [taxon 137693], Bacteria Latreille et al. 1825 (Bacteria stick insect, genus) [taxon 629395], Chrysanthemum x morifolium (florist's chrysanthemum, species) [taxon 41568], Kaempferia galanga (galangal, species) [taxon 97750], Aloe vera (acibar, species) [taxon 34199], Cannabis sativa (species) [taxon 3483], Actinomyces (genus) [taxon 1654], watermelon [taxon 260674], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Mus musculus (house mouse, species) [taxon 10090], Escherichia coli (E. coli, species) [taxon 562], Angelica dahurica (species) [taxon 48101]

## Full text

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## Figures

6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12946673/full.md

## References

152 references — full list in the complete paper: https://tomesphere.com/paper/PMC12946673/full.md

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Source: https://tomesphere.com/paper/PMC12946673