Dry eye disease (DED) is a progressive ocular disorder in which chronic inflammation and oxidative stress synergistically damage ocular tissues and impair vision. While topical anti-inflammatory and artificial tears therapies are the standard treatment for DED, their long-term application is limited by adverse effects and poor patient compliance. Emerging evidence suggests that systemic redox dysregulation contributes to DED pathogenesis, highlighting the potential of oral antioxidant intervention as a disease-modifying strategy. However, the clinical translation of oral antioxidants has been constrained by poor bioavailability and rapid metabolic clearance. Herein, a coral-like resveratrol nanocomplex was fabricated with a composite natural carrier of sericin and dipotassium glycyrrhizinate through a simple pH-ultrasonic-shifting method in aqueous solution, enabling effective oral delivery of this potent polyphenolic antioxidant. This coral-like nanocomplex markedly enhanced gastrointestinal stability and systemic exposure of resveratrol, increasing oral bioavailability by approximately 6.62-fold and ocular accumulation by 2.49-fold. The nanocomplex exerted robust ocular and systemic antioxidant effects and protected against experimental DED in mice. Oral administration of this nanocomplex protected against benzalkonium chloride (BAC)-induced corneal epithelial damage, tear film dysfunction, and inflammatory responses. Mechanistically, the nanocomplex alleviated oxidative damage through ocular and systemic redox homeostasis. Rather than acting solely on the ocular surface, this orally nanomedicine may provide complementary therapeutic benefits through ocular and systemic redox regulation, while also being associated with modulation of gut microbiota and metabolic profiles. These findings support oral redox intervention as a promising complementary strategy for protecting against the DED, particularly for reducing the burden of prolonged topical treatment.
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