Double-Layer Nucleoside-Microneedles Co-Delivering Dexamethasone Vesicles and Adenosine Overcome Pseudomembrane Barriers for the Treatment of Oral Ulcer

Oral ulcers are common, painful mucosal lesions that significantly impair patients’ quality of life. The dynamic and moist oral environment, pseudomembrane formation, and limitations of corticosteroid therapies present ongoing clinical challenges. To address these important challenges, we developed double-layer microneedles integrating three functional components: a rapidly dissolving poly(vinyl alcohol) (PVA) substrate for immediate mucosal adhesion, nucleoside-based microneedles for pseudomembrane penetration and oxidative stress relief, and dexamethasone-loaded polymer vesicles (Dex-PVs). The vesicle improves the bioavailability of dexamethasone and enables a slow, sustained release, enhancing its therapeutic effects. Nucleoside microneedles, incorporating adenosine, synergistically enhance anti-inflammatory and analgesic effects by reducing the release of inflammatory cytokines and decreasing neuronal excitability and reverse the glucocorticoid-induced inhibition of cell migration by promoting CD31 and Ki67 expression. In vivo experiments confirmed that the microneedle reduced the ulcer area to 6.3% after 9 days of treatment (a 69.3% reduction compared to commercial formulations), with significant analgesic effects. This multiscale engineering approach addresses key challenges in oral drug retention, pseudomembrane penetration, and healing regulation, offering a paradigm for the treatment of mucosal diseases.