Cubosomes as Advanced Nanocarriers for Oral Ulcer Treatment: A Review on Their Role in Enhancing Therapeutic Activity

Oral ulcers are painful inflammatory lesions of the oral mucosa that interfere with eating, speaking, swallowing, and overall quality of life. Recurrent aphthous stomatitis, traumatic ulcers, chemically induced ulcers, and inflammatory mucosal lesions are commonly encountered forms. Although topical corticosteroids, antiseptics, local anesthetics, protective gels, and herbal preparations are widely used, their therapeutic action is frequently limited by rapid salivary washout, short mucosal residence time, poor penetration, enzymatic degradation, and the need for frequent application. Recent advances in oral mucosal drug delivery have therefore focused on mucoadhesive and nanocarrier-based systems that can improve drug retention, local bioavailability, and sustained therapeutic action. Cubosomes are lipid-based, self-assembled, bicontinuous cubic phase nanoparticles composed of amphiphilic lipids such as glyceryl monooleate or phytantriol and stabilizers such as Poloxamer 407. Their unique internal architecture contains interpenetrating aqueous channels separated by lipid bilayers, enabling simultaneous incorporation of hydrophilic, lipophilic, and amphiphilic molecules. This makes cubosomes highly suitable for delivering anti-inflammatory, antimicrobial, antioxidant, analgesic, and wound-healing agents to oral ulcer sites. When incorporated into a mucoadhesive gel, cubosomes may improve mucosal adhesion, protect unstable drugs or phytoconstituents, sustain release, enhance local penetration, reduce dosing frequency, and maintain therapeutic concentration at the ulcer surface. Herbal extracts such as Psidium guajava leaf extract may particularly benefit from cubosomal delivery because their flavonoid, tannin, and phenolic constituents have reported anti-inflammatory, antioxidant, antimicrobial, and wound-healing potential. Overall, cubosome-loaded mucoadhesive gels represent a promising advanced approach for oral ulcer therapy, although further standardized preclinical and clinical studies are required.