Abstract / Summary
Abstract Alopecia areata (AA) is an autoimmune disease driven by the collapse of hair follicle immune privilege. Currently available treatments showed limited efficacy and high recurrence rates. Indoleamine 2,3-dioxygenase 1 (IDO1) has been recognized as critical enzyme by catalyzing tryptophan-to-kynurenine conversion to induce immunosuppression and maintain immune privilege. Aberrant IDO1 inactivation disrupts hair follicle immune privilege, causing inflammatory follicular damage and subsequent hair loss. Herein, we designed an IDO1-loaded Cu-doped zeolitic imidazolate framework (IDO@Cu/ZIF) to restore tryptophan-to-kynurenine metabolism, thereby rebuilding hair follicle immune privilege for long-term AA management. By mimicking the Cu/Zn centers in natural antioxidant enzymes, Cu/ZIF nanozymes deliver high capability to eliminate excessive reactive oxygen species in AA lesions. Meanwhile, Cu atom-induced upshift of the d-band center enhances substrate adsorption, thereby improving antioxidant performance. In vitro and in vivo experiments confirmed that IDO@Cu/ZIF reconstructs hair follicle immune privilege by restoring the tryptophan/kynurenine axis, thereby promoting hair follicle regeneration and achieving approximately 75% hair coverage. More importantly, IDO@Cu/ZIF treatment maintains long-term immune privilege and effectively suppresses AA recurrence. This study offers mechanistic insights into the rational design of high-performance antioxidant nanozymes and expands their potential applications in autoimmune diseases of AA.