Novel TNF-α-targeting mRNA therapy for sustained psoriasis treatment and relapse prevention by suppressing IL-15-TRM signaling

Psoriasis is an autoimmune skin disease that substantially impairs patients' quality of life and presents clinical challenges due to frequent relapses and adverse effects associated with conventional therapies, including glucocorticoids and immunosuppressants. Although tumor necrosis factor-alpha (TNF-α) inhibitors are widely used as front-line treatments, safer alternatives remain imperative. Here, RET-1-mRNA-LNP, a novel mRNA-based TNF-α inhibitor, was developed and comprehensively evaluated for its therapeutic efficacy in imiquimod (IMQ)-induced psoriasis and relapse mouse model. RET-1-mRNA-LNP demonstrated superior efficacy in reducing erythema, scaling, and epidermal hyperplasia, along with a significant suppression of Th17 cell activity and other immune cell infiltration into lesional skin. Mechanistically, RET-1-mRNA-LNP delayed psoriasis recurrence by suppressing IL-15 production and generation of tissue-resident memory T (T_RM) cells. These findings provide novel insights and a theoretical foundation for developing TNF-α-targeting mRNA-based therapeutics for psoriasis treatment, evoking potential applications in other autoimmune diseases characterized by excessive TNF-α production.