Abstract

Colanic acid, a multifunctional natural bioactive hydrogel with tunable molecular weight, was developed for dry eye therapy. • Colanic acid eye drops showed superior in vivo efficacy against dry eye disease versus sodium hyaluronate eye drops. • Colanic acid modulates calcium influx and key signaling pathways to reduce inflammation, oxidative stress, and apoptosis. Dry eye disease is a multifactorial disorder of the ocular surface characterized by tear film instability, chronic inflammation, oxidative stress, and epithelial damage, ultimately leading to the disruption of ocular surface homeostasis. However, effective therapeutic strategies simultaneously targeting these interconnected pathological processes remain limited. This study aimed to develop colanic acid with tunable molecular weights, a fucose-rich polysaccharide with intrinsic hydrogel-like properties, excellent water-retention capability, and potent anti-inflammatory and antioxidant activities and to explore its use as a natural bioactive hydrogel for ocular surface repair and dry eye therapy. In vitro experiments demonstrated that colanic acid exhibited excellent cytocompatibility and effectively protected human corneal epithelial cells against hyperosmotic stress– and oxidative stress–induced injury by reducing the accumulation of intracellular reactive oxygen species. In a murine dry eye model, the topical administration of colanic acid eye drops markedly promoted corneal epithelial recovery, restored conjunctival goblet cell density, and suppressed ocular surface inflammatory responses and matrix metalloproteinase expression, exhibiting superior therapeutic efficacy compared with clinically used sodium hyaluronate eye drops. Mechanistically, colanic acid restored ocular surface homeostasis by modulating intracellular calcium signaling, improving mitochondrial function, and inhibiting activation of the phosphoinositide 3-kinase/protein kinase B/nuclear factor-κB and mitogen-activated protein kin