Multifunctional selenium nanoplatforms for synergistic ferroptosis inhibition and immune microenvironment remodeling in oral mucositis.

Abstract

Oral mucositis (OM) is a common inflammatory disorder characterized by epithelial barrier destruction, uncontrolled inflammation, and impaired mucosal repair. Despite the complex tissue microenvironment in OM, which is driven by interconnected pathological processes, current therapeutic approaches are hindered by their predominant focus on single factors. In this study, we identified ferroptosis as a key driver of OM progression through clinical sample analysis and mechanistic validation, revealing that disrupted selenium metabolism and decreased Glutathione Peroxidase 4 (GPX4) expression promote lipid peroxidation and epithelial cell death. To address this, we developed a poly (5-hydroxytryptamine)-functionalized selenium nanoparticle system (PST-SeNPs) that integrates mucosal adhesion, antioxidation, and immunoregulation capabilities. The PST-SeNPs exhibited strong mucosal adhesion and deep tissue penetration in oral ulcer regions. Mechanistically, the system synchronously inhibited ferroptosis by restoring GPX4 activity, alleviating oxidative stress, and modulating macrophage polarization toward an anti-inflammatory phenotype, thereby reconstructing the epithelial and immune microenvironments. In vitro and in vivo studies demonstrated that PST-SeNPs effectively reversed the pathological cycle of "oxidative stress-ferroptosis-inflammation," accelerated mucosal healing, and significantly improved therapeutic outcomes compared to conventional selenium formulations. This work establishes the pivotal role of selenium metabolism imbalance and ferroptosis in OM progression and proposes an integrated nanoplatform that synergistically targets epithelial and immune microenvironments.