Designing Enzyme-Sensitive Polymers as Site-Specific Delivery Systems for Ocular Therapies

Abstract Enzyme-responsive polymers represent a promising strategy for overcoming the anatomical and physiological barriers that limit drug delivery to the eyes. These materials can be adapted to enable enzyme-dependent polymer degradation and drug release by incorporation of enzyme-cleavable motifs, such as peptide, polysaccharide, ester, and phosphoramidate linkages. Loading them into hydrogels, nanoparticles, nanogels, drug-eluting contact lenses, and injectable implants may enhance ocular residence time and enable sustained or on-demand drug delivery, perhaps with increased spatial and disease-associated selectivity when differences in enzyme activity and substrate accessibility are sufficient in preclinical models. This Review presents the advances in enzyme-sensitive polymer systems for ophthalmic applications from 2019 to 2025. It covers relevant ocular barriers and enzymatic microenvironments, key polymer chemistries, structure–degradation–release relationships, delivery platforms, and preclinical applications in corneal, anterior segment, and posterior segment diseases. Major challenges associated with enzyme variability, biodistribution, safety, manufacturing, and regulatory translation are also discussed in this Review. To summarize, enzyme-responsive polymers provide a promising strategy for developing more controllable and flexible ocular delivery systems for drugs.