In situ self-assembling rebamipide-based eye drops to promote secretion of mucin for treatment of dry eye

Rebamipide is effective for dry eye management, but its insolubility limits formulation development. An optimal design is crucial for patient comfort and maximizing bioavailability. Here we covalently conjugate rebamipide with a peptide motif (FFFYpEH) to generate a peptide-drug conjugate that dramatically improves solubility and enables <i>in situ</i> self-assembly. After topical instillation, the conjugate undergoes enzyme-instructed self-assembly, leading to enhanced drug retention (>25 min) on the ocular surface. <i>In vitro</i>, the conjugate stimulates MUC1 secretion in human corneal epithelial cells and MUC5AC secretion in human conjunctival epithelial cells. In a murine dry eye model, the conjugate demonstrates superior therapeutic efficacy over commercial rebamipide eye drops (Mucosta®), as evidenced by significant symptom alleviation, enhanced corneal epithelial repair, restored tear secretion, and increased conjunctival goblet cell density. Relative to the 14-day non-intervention, treatment of the conjugate results in a threefold increase in corneal epithelium thickness, achieving normal levels. Tear secretion rises nearly fivefold, and conjunctival goblet cell density triples, reaching values comparable to a healthy cornea. Overall, this work addresses the limitations of existing drugs by developing a strategy that not only enhances drug solubility but also promotes ocular retention through <i>in situ</i> self-assembly, thereby offering a promising clinical solution for dry eye management.