Cationic interfacial engineering of ceria nanotherapeutics enables epithelial barrier penetration and stromal fibrosis inhibition in corneal alkali burns

Corneal alkali burns frequently lead to severe pathological manifestations (including oxidative stress and inflammatory response) and dysregulated matrix remodeling-associated stromal fibrosis. Current treatments mainly target inflammation but remain insufficient for preventing fibrotic scarring and enhancing corneal clarity. To address this limitation, a natural anti-fibrotic proteoglycan i.e., decorin (DCN) was conjugated to quaternary ammonium (QA)-modified nanoceria (Ce) as multifunctional metallic therapeutics (Ce-QA/DCN). The biofunctionalized nanomaterials exhibited favorable physicochemical stability and good ocular biocompatibility. Our results demonstrated that the conjugated DCN can preserve its ability to inhibit collagen fibrillogenesis and downregulate fibrosis-associated signaling pathways. In a rat model of alkali burns, topical administration of Ce-QA/DCN markedly improved corneal tissue transparency and promoted stromal architectural restoration as compared with conventional pharmacological treatment (dexamethasone). The combination of ceria-mediated redox regulation and DCN-mediated fibrotic inhibition enables simultaneous alleviation of pathological manifestations and enhancement of matrix remodeling during corneal wound healing. In summary, the biomaterial-based nanomedicine may provide a promising therapeutic strategy for managing severe corneal injuries and fibrosis-related ocular surface disorders. STATEMENT OF SIGNIFICANCE: Owing to their tunable surface properties and intrinsic biological activities, metallic nanomaterials have been considered promising platforms for ocular delivery and therapy; however, achieving effective corneal epithelial penetration while simultaneously regulating complex ocular pathological process remains a major challenge. This work presents the first report on rational design of ceria-based (quaternary ammonium/decorin-functionalized) nanotherapeutics for tailoring the structure-function relationships toward effective treatment of corneal alkali burn. Integrating cationic interface engineering with antagonist conjugation is demonstrated to critically govern permeability and biocompatibility of nanoparticles, indicating that the optimized formulations can enhance epithelial barrier penetration and inhibit stromal oxidation/inflammation/fibrosis. In vivo, such a biomaterial design achieves ∼92% reduction in corneal haze, highlighting its potential for treating eye injuries and promoting tissue remodeling.