Surface-engineered hydrophobic hydrogels via cholesterol micelle rearrangement for robust wet adhesion and oral mucositis therapy

Oral mucositis (OM), a prevalent and debilitating complication in patients undergoing chemotherapy or radiotherapy, is characterized by persistent neuropathic pain and impaired food intake. Conventional treatments are often limited by poor mucosal adhesion in the dynamic, saliva-rich oral environment. To address this challenge, we developed a mussel-inspired robust wet adhesive hydrogel via cholesterol micelle rearrangement, in which negatively charged catechol-functionalized hyaluronic acid (HD) forms a polyelectrolyte network with positively charged polyethyleneimine (PEI), triggering cholesterol-micelle chain rearrangement and directional surface micelle aggregation to achieve hydrophobic hydrogel surface. This mechanism enables robust wet adhesion (>10 kPa in artificial saliva) without pre-treatment or toxic crosslinkers. The hydrogel with mechanical compliance ensures seamless adaptation to oral tissue dynamics, functioning as a protective barrier against food-induced mechanical/chemical insults while enhancing lidocaine bioavailability. Synergizing catechol-mediated antioxidative activity (DPPH radical scavenging: >70 %) with sustained lidocaine release, the hydrogel can relieve pain and accelerate mucosal repair in 7 days by promoting epithelial regeneration, angiogenesis, and neurogenesis. This work presents a novel strategy for designing orally adaptive biomaterials, merging wet adhesion, drug delivery, and tissue remodeling into a single platform for effective OM management.