Single‐Atom Catalysts with Isolated Cu1‐N4 Sites for Atopic Dermatitis Cascade Catalytic Therapy via Activating PPAR Signaling

Abstract Atopic dermatitis (AD) is one of the most common allergic skin disorders affecting over 230 million people worldwide, while safe and efficient therapeutic options for AD are currently rarely available. Reactive oxygen species (ROS) accumulation plays a key role in AD's disease progression. Therefore, a novel single‐atom catalyst is designed with isolated Cu 1 ‐N 4 sites anchored on carbon support (Cu 1 ‐N 4 ISAC), featuring triple antioxidant enzyme‐mimicking activities, for efficient AD cascade catalytic therapy (CCT). The excellent superoxide dismutase (SOD)‐, glutathione peroxidase (GPx)‐, and ascorbate peroxidase (APx)‐like activities of Cu 1 ‐N 4 ISACs enable the sequential conversion of O 2 • − to H 2 O 2 and then to harmless H 2 O, thereby protecting keratinocytes from oxidative stress damage. Notably, two novel experimental methods are developed to directly prove the SOD‐GPx and SOD‐APx cascade catalytic activities for the first time. In vivo experiments show that Cu 1 ‐N 4 ISACs are more potent than a recommended typical medicine (halcinonide solution). Additionally, RNA sequencing and bioinformatic analysis reveal that Cu 1 ‐N 4 ISACs reduce inflammation and inhibit ROS production by activating PPAR signaling, which is aberrantly reduced in AD. Therefore, the synthesized catalytic medicine offers an alternative to alleviate AD and has the potential to serve as PPAR agonists for treating similar diseases.