A ROS‐Responsive and Mucoadhesive Thermosensitive Hydrogel Encapsulated with Mizoribine for Synergistic Dry Eye Therapy

ABSTRACT Dry eye disease (DED) is a multifactorial disorder characterized by intricate pathogenesis, necessitating a multi‐target synergistic intervention strategy. Current anti‐inflammatory drugs for DED are limited by low bioavailability, ocular irritation, and inadequate relief. Herein, we propose a multifunctional hydrogel encapsulating Mizoribine, a small‐molecule water‐soluble immunosuppressant. The formulation undergoes in situ gelation on the ocular surface, forms a mucin‐adhered coating, and responds to pathological oxidative stress to enable controlled drug release. In vitro studies demonstrate the formulation effectively mitigates cellular oxidative stress by scavenging ROS and upregulating antioxidant factors. It also protects mitochondrial function, reduces apoptosis, and modulates macrophage polarization. In vivo, topical application of the hydrogel markedly alleviates clinical signs of disease. It also suppresses ocular surface inflammation and reverses conjunctival goblet cell loss. Molecular and cellular analyses indicate the hydrogel exerts its therapeutic effects primarily through antioxidative, anti‐inflammatory, and macrophage‐modulating mechanisms. Importantly, the formulation exhibits an excellent biosafety profile. Our findings highlight that this multifunctional hydrogel serves as a potent, convenient, and safe nanotherapeutic platform. By integrating ROS‐responsive, thermosensitive, and sustained drug‐release properties with antioxidant, anti‐inflammatory, and immunomodulatory functions, this formulation simultaneously targets multiple pathological pathways, offering a promising avenue for clinical translation in treating chronic ocular surface diseases.