Microenvironment-Responsive Drug Delivery Systems for Ocular Surface Diseases: Mechanisms, Applications, and Translational Challenges.

Vision impairment not only compromises patients' quality of life but also imposes a substantial societal and economic burden. Conventional ophthalmic formulation is hindered by ocular physiological barriers, leading to low bioavailability and necessitating frequent administration. To overcome these limitations, novel microenvironment-responsive drug delivery systems (MR-DDSs), have emerged as a highly promising strategy. This review aims to systematically summarize recent advances in MR-DDSs for treating ocular diseases, providing insights for clinicians and researchers. Firstly, we elucidated the characteristics of the ocular microenvironment under normal and pathological conditions, including factors such as temperature, pH, and the levels of ions, reactive oxygen species (ROS), and enzymes. Subsequently, we introduced the categories, properties, and molecular mechanisms of stimulus-responsive polymers, followed by a summary of preparation methods, characterization techniques and performance metrics for major systems. Then, we summarized the application and therapeutic efficacy of MR-DDSs in managing a range of common ocular surface diseases, including dry eye disease, infectious keratitis, and corneal neovascularization. Finally, we critically analyzed the obstacles to clinical translation and propose promising avenues for future research. This review offers a comprehensive framework bridging material design, performance evaluation, and clinical translation, providing actionable insights for both clinicians and researchers in the field.