Gold Nanoparticles‐Embedded Mn/Zn‐MOF with Enhanced Antioxidant Activities for Treating Atopic Dermatitis

ABSTRACT Atopic dermatitis (AD) is a skin disease characterized by impaired barrier function and immune dysregulation, in which oxidative stress imbalance plays a key pathogenic role. Current clinical therapies for AD treatment primarily target immune and inflammatory responses, but rarely address direct clearance of reactive oxygen species (ROS). To correct this imbalance, a multi‐enzyme‐mimetic nanocomposite, an Au@Mn/Zn bimetallic metal–organic framework (Au@Mn/Zn‐MOF; AMZM) is constructed. Manganese sites in AMZM reversibly cycle among Mn(II/III/IV), thereby mimicking superoxide dismutase (SOD) and catalase (CAT) activities. Density functional theory calculations confirm that incorporated gold nanoparticles (AuNPs) optimize the electronic structure of Mn sites by stabilizing the key Mn(III) intermediate and lowering energy barriers, enabling efficient cascade scavenging of O 2 · − and H 2 O 2 . In cellular models, AMZM suppresses ROS, stabilizes mitochondrial function, and downregulates inflammatory cytokines. In a 2,4‐dinitrochlorobenzene (DNCB)‐induced AD mouse model, topical application of polyvinyl alcohol (PVA)‐coated AMZM significantly alleviates skin lesions, restores barrier function, and reduces immune infiltration. Transcriptomic and mechanistic studies further indicate that AMZM exerts antioxidant and anti‐inflammatory effects through direct ROS scavenging and activation of the FOXO3 pathway. These results support AMZM as a nanotherapeutic strategy for AD treatment.