Hyaluronic acid-based osmolality-responsive immediate-release microneedles co-loading baicalein and astaxanthin for oral ulcer therapy.

Oral ulcers, a prevalent mucosal disorder, are clinically managed by topical corticosteroids and immunosuppressants to alleviate symptoms. However, conventional therapies suffer from suboptimal drug bioavailability, inconsistent efficacy, and potential adverse effects. To address these limitations, using natural carbohydrate polymer hyaluronic acid (HA) with excellent biocompatibility, as the main substrate, we constructed the osmolality-responsive immediate-release microneedles (MNs) platform (GA@BA&Ast MNs) co-loading baicalein (BA) and astaxanthin (Ast) for oral ulcer therapy, which effectively addresses traditional treatment bottlenecks via responsive immediate-release and efficient absorption. The platform's core innovation lies in its dynamically controllable release mechanism, which is triggered specifically by the oral microenvironment. Its osmolality-responsive mechanism, relying on HA-Ca2+ dynamic coordination network dissociation in oral fluid, enables rapid disintegration and delivery speed superior to conventional microneedles, with good mechanical strength for irritation-free mucosal penetration and 85.3%/87.1% cumulative BA/Ast release within 20 min. In the rat model, GA@BA&Ast MNs significantly accelerated ulcer healing, increased collagen deposition and VEGF expression by 41.22% and 47.05%, and exerted complementary antibacterial, anti-inflammatory, and ROS scavenging effects by promoting epithelial migration and angiogenesis. This responsive MNs platform overcomes the limitations of hydrophobic drug delivery, providing a promising universal strategy for localized orofacial diseases, such as oral ulcers, oral fibrosis, and oral cancer.