Self-Oxidatively Crosslinked Sprayable Hydrogel for Microenvironment Remodeling and Accelerated Healing of Recurrent Aphthous Ulcers

Recurrent aphthous ulcer (RAU) is a prevalent inflammatory disorder of the oral mucosa, characterized by a persistent “vicious cycle” of excessive oxidative stress, dysregulated immune responses, and impaired tissue regeneration. Effective clinical management remains challenging due to the dynamic and hydrated oral environment, which severely limits drug retention and multi-target therapeutic efficacy. Herein, we developed a multifunctional, sprayable hydrogel (PDS Gel) using a hierarchical “oxygen-limited initiation – oxygen-controlled progression” crosslinking strategy, integrating polygalacturonic acid (PGA), dopamine (DA), and salidroside-derived carbon dots (Sal-CDs). The PDS Gel achieves rapid in situ solidification and exhibits certain mucoadhesive properties, allowing attachment to the wet mucosal surface shortly after spraying. Mechanistically, the hydrogel exhibits potent reactive oxygen species (ROS) scavenging capacity and intrinsic antibacterial activity, effectively remodeling the pathological wound microenvironment. Crucially, PDS Gel promotes macrophage polarization from a pro-inflammatory M1 phenotype toward a pro-regenerative M2 phenotype, thereby suppressing excessive inflammatory cascades. Simultaneously, it restores fibroblast-mediated extracellular matrix (ECM) remodeling and enhances endothelial cell-driven angiogenesis. In vivo evaluations using both oral mucosal and full-thickness skin defect models demonstrate that PDS Gel significantly accelerates wound closure, facilitates epithelial reconstruction, and promotes orderly collagen deposition. Collectively, this self-oxidatively crosslinked immunomodulatory hydrogel provides a promising biomaterial paradigm for the precision therapy of RAU and other complex mucosal lesions. • Hierarchical crosslinking enables a sprayable and strongly adhesive hydrogel. • The hydrogel regulates macrophage polarization and attenuates inflammation. • Promotes fibroblast migration and endothelial angiogenesis. • Enhances ECM remodeling and accelerates healing of recurrent ulcers. • Accelerated healing is validated in both oral ulcer and skin wound models.