A ROS ‐Responsive Hydrogel Microneedle System Co‐Delivering Tofacitinib and Azelaic Acid for Enhanced Targeted Therapy of Rosacea

ABSTRACT Rosacea is a chronic inflammatory skin condition primarily affecting the face, characterized by symptoms such as persistent redness, visible blood vessels, papules, and pustules. Current treatments, including topical agents and systemic antibiotics, are often limited by poor skin penetration, local irritation, or the risk of systemic adverse effects and antibiotic resistance. This study designed, fabricated, and evaluated a novel ROS‐responsive hydrogel microneedle (MN) system for the co‐delivery of tofacitinib (a JAK inhibitor) and azelaic acid (A ZA) to treat rosacea. The hypothesis was that this Tofa/AZA@HPA‐MN platform would enable triggered drug release in the high‐ROS environment of inflamed skin, enhancing therapeutic efficacy and safety compared to conventional topical delivery. Topical tofacitinib and AZA were found to ameliorate LL37‐induced murine rosacea‐like inflammation, partly via JAK/STAT inhibition. A ROS‐responsive hydrogel (HPA) was synthesized and fabricated into robust MNs, demonstrating effective skin penetration and retention. In vitro, these MNs displayed accelerated drug release under oxidative conditions and protected keratinocytes from H 2 O 2 ‐induced stress. In vivo, the Tofa/AZA@HPA‐MNs proved superior to conventional topical Tofa + AZA and empty MNs, significantly reducing inflammation, tissue ROS levels, and JAK/STAT activation in a rosacea model. Crucially, safety assessments revealed no significant systemic toxicity, addressing the major translational concern regarding the systemic risks of JAK inhibitors. The developed system offers a promising, safe, and more effective targeted therapeutic strategy for rosacea by enabling triggered drug release directly within the inflamed skin.