Synergistic nanosenolytic therapy reverses age-related dry eye disease by targeting cellular senescence and oxidative stress.

Abstract

Dry eye disease (DED) is a prevalent, age-related ocular disorder that severely impairs vision and quality of life. Age-related cellular senescence drives disease progression through the senescence-associated secretory phenotype (SASP), which establishes a self-perpetuating cycle of oxidative stress and chronic inflammation. However, current therapeutic options are insufficient to directly disrupt this pathogenic feedback loop. To address this, we developed a dynamically responsive polypeptide-based nanosenolytic eye drop co-encapsulating quercetin and superoxide dismutase (SOD). Quercetin serves a dual function as both an anti-aging agent and a hydrophobic motif driving nanocarrier self-assembly, enabling efficient SOD loading and pH-responsive endosomal escape. This nanoplatform demonstrated superior corneal permeability compared to free SOD, leading to suppressed oxidative stress and apoptosis, restored lacrimal gland function, and reversed key DED manifestations. Furthermore, by effectively attenuating SASP activity in aged DED models, the treatment showed profound disease-modifying efficacy. Collectively, this work establishes local nanosenolysis as a potent therapeutic strategy for multifactorial DED by simultaneously targeting oxidative damage and cellular senescence.