Dental pulp stem cell-derived exosomes attenuate psoriatic inflammation by restoring epithelial redox homeostasis via...

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.

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.

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.

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.