Dual‐Responsive Chitosan‐Grafted PNIPAAm Hydrogel Eye Drop Incorporating Insulin‐Imprinted Microgels for Dry Eye Syndrome Treatment

Dry eye syndrome (DES) happens as a result of inadequate tear secretion or excessive evaporation, which leads to ocular surface irritation and damage. A major therapeutic challenge is maintaining effective drug concentrations, as topical formulations are rapidly cleared by blinking and tear turnover. To address this limitation, we developed a dual pH‐ and temperature‐responsive composite hydrogel composed of chitosan (Cs)‐grafted poly‐N‐isopropylacrylamide (PNIPAAm)‐ CPN integrated with alginate‐based insulin‐imprinted microgels (IMIP). Incorporation of IMIP particles allowed tuning of rheology, swelling behavior, wettability, and biodegradation while preserving proper topical administration. Microgel addition increased viscosity from 3.1 mPa·s (CPN‐IMIP10) to 37.3 mPa·s (CPN‐IMIP35), and the sol–gel transition between 25 and 37°C enabled flowability at room temperature followed by rapid gelation on the ocular surface. All CPN‐IMIP hydrogels exhibited elastic‐dominant behavior (G′ > G″), confirming formation of a stable, shear‐resistant network. Insulin release was tunable: at pH 6.4 and 25°C, diffusion governed delivery (29.8 ± 3.6% at 48 h), whereas at pH 7.4 and 37°C, swelling‐controlled release predominated (54.4 ± 4.8%). The composite hydrogels supported human corneal epithelial cell viability and enhanced tear secretion, preserved corneal integrity, and reduced inflammation in a rat DES model. This system provides a minimally invasive, long‐acting therapeutic platform for DES.