Smart Responsive Hydrogels for Dry Eye Disease: Microenvironment-Sensing Drug Delivery and Therapeutic Translation.

Purpose: To review smart responsive hydrogels for dry eye disease (DED), focusing on pharmacological performance, disease relevance, safety, and translational feasibility.

Methods

A narrative literature search was conducted in PubMed, Web of Science, Scopus, and Google Scholar up to June 11, 2026, using terms for DED, hydrogels, and ocular drug delivery. Studies were selected based on relevance to DED pathophysiology, hydrogel responsiveness, and translational safety.

Results

Thermosensitive and ion-sensitive hydrogels are the most practical near-term options because they enable drop-like administration and rely on simple physiological triggers. ROS- and enzyme-responsive systems offer stronger mechanistic links to DED pathology but face challenges in trigger variability, safety, and manufacturing complexity. Photoresponsive platforms allow spatiotemporal control but require device-dependent activation. Multi-stimuli systems integrate retention and disease-triggered release, though their added complexity must be justified by measurable therapeutic benefit. Most DED-specific responsive hydrogels remain at the preclinical stage; human evidence mainly concerns familiar device formats, not the responsive formulations themselves.

Conclusion

Smart responsive hydrogels can tailor drug delivery to ocular surface conditions, but evidence maturity varies across platforms. Thermosensitive and ion-sensitive gels are the most clinically plausible near-term candidates. ROS-responsive, enzyme-responsive, and multi-stimuli systems better engage DED biology but need stronger validation. Translation depends on direct comparator studies, phenotype-matched endpoints, long-term ocular safety, scalable sterile manufacturing, and appropriate regulatory strategies.