Smart In Situ-Forming Ocular Therapeutics for Dry Eye Disease: Bridging Biomaterials, Nanotechnology, and Clinical Translation.

Dry eye disease (DED) is a multifactorial inflammatory condition of the ocular surface that significantly impairs quality of life through tear film instability and chronic irritation. Despite the prevalence of DED, conventional topical therapies are hindered by poor ocular bioavailability (< 7%) due to rapid precorneal clearance and restrictive anatomical barriers. Stimuli-responsive in situ forming systems have emerged as a transformative strategy to overcome these limitations by undergoing a "sol-to-gel" transition in response to physiological triggers such as temperature, pH, or ionic strength. This review provides a comprehensive analysis of recent advancements in "smart" ocular therapeutics, specifically focusing on the integration of nanocarriers within stimuli-responsive hydrogel matrices. Furthermore, we discuss the role of redox- and enzyme-responsive platforms in addressing the oxidative stress and enzymatic imbalances characteristic of the DED microenvironment. By bridging the gap between innovative biomaterials and clinical translation, this review identifies the pathways for next-generation precision medicine in ophthalmology, offering a roadmap to improve patient compliance and long-term therapeutic outcomes in DED management.