Adhesive hydrogel delivering ALA prevents the malignant transformation of oral leukoplakia

Photodynamic therapy (PDT) has shown promising efficacy for oral leukoplakia (OLK); however, its effectiveness is often compromised by the dynamic and wet oral environment, which impedes drug retention and complicates the maintenance of therapeutic concentrations. To overcome these limitations, we developed a mucoadhesive hydrogel composed of acrylic acid (AA), chitosan (CHI), and polydopamine for the controlled delivery of 5-aminolevulinic acid (ALA). The resulting ALA-loaded hydrogel (ALA-Gel) was synthesized via chemical cross-linking and demonstrated excellent wet adhesion capable of withstanding salivary flow, alongside sustained ALA release profiles. In vitro, ALA-Gel-mediated PDT markedly enhanced reactive oxygen species (ROS) generation and induced potent cytotoxicity in leukoplakia cells, while maintaining high biocompatibility with normal human keratinocytes. In a rat OLK model, the hydrogel achieved prolonged intraoral retention. Upon laser irradiation (632 nm, 100 mW·cm -2 , 100 J·cm -2 ), both clinical and histopathological assessments confirmed a significant suppression of malignant progression. Furthermore, preliminary clinical trials (n = 30) demonstrated superior therapeutic outcomes compared to conventional treatments. Collectively, this hydrogel-based strategy addresses key challenges in oral PDT, offering a viable and translatable option for OLK management. • A novel adhesive hydrogel system was developed for sustained delivery of 5-aminolevulinic acid (ALA), enhancing photodynamic therapy (PDT) efficacy for oral leukoplakia (OLK). • The ALA-loaded hydrogel demonstrated excellent wet adhesion, biocompatibility, and potent reactive oxygen species generation, effectively inducing leukoplakic cell death in vitro and in vivo. • Clinical trials confirmed superior therapeutic outcomes and patient comfort compared to conventional ALA-PDT, highlighting its translational potential for preventing OLK malignant transformation.