Targeting ALOX15 with a ROS‐Responsive Lipid Nanoparticle for the Treatment of Allergic Conjunctivitis and Its Comorbidity Dry Eye Disease

ABSTRACT Allergic conjunctivitis (AC) and its frequent comorbidity, dry eye disease (DED), represent prevalent ocular surface inflammatory disorders, significantly impairing patients’ visual quality. Arachidonic acid 15‐lipoxygenase (ALOX15) emerges as a common pathogenic factor, mediating inflammatory responses and lipid peroxidation in both conditions. Here, a therapeutic strategy is designed based on reactive oxygen species‐responsive lipid nanoparticles loaded with siALOX15‐5 (rLNP@siALOX15‐5). This strategy enhances ocular penetration and sustains silencing of ALOX15, alleviating the symptoms of AC by executing a dual mechanism. It simultaneously suppresses multiple signaling pathways involved in the inflammatory response, particularly cytokine‐cytokine receptor interaction and chemokine signaling pathway, while potently inhibiting lipid peroxidation and enhancing antioxidant defenses. In an autoimmune‐related DED mice model, rLNP@siALOX15‐5 alleviates clinical symptoms and restores ocular surface homeostasis. Moreover, in the AC and DED comorbid model, it outperforms cyclosporine A and TobraDex monotherapies, achieving effects comparable to their combination. These studies not only validate the value of ALOX15 as a common therapeutic target for both AC and DED but also establish rLNP@siALOX15‐5 as an effective strategy for treating these two associated ocular surface diseases through its dual‐regulatory mechanism.