Dental pulp stem cell–derived exosomes attenuate psoriatic inflammation by restoring epithelial redox homeostasis via a miR-1246/miR-17-3p–GPX2–NF-κB axis

BACKGROUND: Psoriasis is driven by sustained epidermal inflammation tightly coupled to dysregulated redox homeostasis. Although current systemic therapies are effective, their long-term use is limited by safety concerns. Dental pulp stem cell-derived exosomes (DPSC-Exo) have emerged as promising immunomodulatory, cell-free therapeutics, yet their role in regulating epithelial redox-inflammatory balance remains undefined. METHODS: The therapeutic effects of DPSC-Exo were evaluated using an imiquimod-induced mouse model of psoriasis, ex vivo human skin explants, and M5-stimulated primary human keratinocytes. Transcriptomic profiling, immunostaining, and gain- and loss-of-function analyses were performed to define the underlying molecular mechanisms. RESULTS: Topical administration of DPSC-Exo markedly reduced epidermal hyperplasia, neutrophil infiltration, angiogenesis, and expression of key psoriatic mediators, including IL-23 A, IL-17 A, and antimicrobial peptides. These effects were consistently reproduced in human skin explants and keratinocyte models. RNA-sequencing identified glutathione peroxidase 2 (GPX2), a key epithelial antioxidant enzyme, as a prominently upregulated target following DPSC-Exo treatment. Restoration of GPX2 suppressed NF-κB activation and downstream cytokine production, whereas GPX2 silencing abolished the protective effects of DPSC-Exo. Mechanistically, two exosomal microRNAs, miR-1246 and miR-17-3p, were required for GPX2 induction and mediated the majority of the observed anti-inflammatory responses. CONCLUSIONS: These findings identify a previously unrecognized miRNA-GPX2-NF-κB axis through which DPSC-Exo restore epithelial redox-inflammatory homeostasis. Our study supports DPSC-Exo as a promising cell-free therapeutic candidate for psoriasis and highlights epithelial redox regulation as a potentially targetable mechanism for inflammatory skin diseases.