Dual-Action Cationic Nanoparticle Eye Drops Synergistically Disrupt the Pathological Cycle of Dry Eye Disease via ROS-Scavenging and Inflammation Inhibition

Dry eye disease (DED) is an increasingly prevalent ocular surface disorder that causes discomfort and, in severe cases, visual impairment. A central feature of DED is a self-perpetuating oxidative stress-inflammation cycle, in which excessive reactive oxygen species (ROS) production initiates and sustains inflammatory injury. Treatments directed only at inflammation may therefore provide incomplete control. Here, we developed self-assembled PGED-TEMPO-2/fibronectin (FN) nanoparticle eye drops comprising a ROS-scavenging cationic polymer and an extracellular matrix protein with reported immunomodulatory activity. The cationic surface may favor interaction with negatively charged corneal mucins, thereby contributing to prolonged ocular surface retention. In vitro and in vivo, PGED-TEMPO-2/FN reduced ROS accumulation, preserved mitochondrial membrane potential, lowered pro-inflammatory cytokine expression, modulated macrophage polarization, and decreased apoptosis. In a benzalkonium chloride-induced mouse model of DED, the formulation reduced ocular surface inflammation, promoted corneal epithelial repair, and produced greater mean improvements than cyclosporine under the tested regimen. Thus, PGED-TEMPO-2/FN integrates antioxidant activity, protein delivery, and ocular retention in a single topical platform for DED treatment.