Synthetic Bilirubin‐Based Nanomedicine Alleviates Atopic Dermatitis by Reducing Oxidative Stress and Modulating Immune Responses

Abstract Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a growing prevalence worldwide. Topical corticosteroids and non‐steroidal calcineurin inhibitors (CNIs) are used as first‐line therapies for AD, but various side effects limit their long‐term use. Here, the first synthetic bilirubin(IIIα)‐derived nanoparticle is reported, designated BRNP(IIIα), and shows that it exhibits robust antioxidative and immunomodulatory effects and effectively reduces the clinical symptoms of AD upon topical treatment. BRNP(IIIα) in 1% high molecular weight hyaluronic acid (BRNP(IIIα)/HA) readily infiltrates into the dermis layer, notably downregulates disease‐associated reactive oxygen species (ROS) and inflammatory chemokines and cytokines, and suppresses the recruitment of leukocytes and mast cells to AD‐induced lesions. BRNP(IIIα)/HA also significantly reduces the tissue‐resident memory T cell population, suggesting that it may inhibit recurrence. Furthermore, BRNP(IIIα)/HA does not induce any adverse effect related to skin irritation/sensitization or eye irritation in human tissue. Collectively, the findings suggest that BRNP(IIIα)/HA may be useful as an alternative to corticosteroids or CNIs for the safe, effective, and long‐term topical treatment of AD.