Thermogelling lacrimal duct-applied therapeutic platform for dry eye syndrome.

Dry eye syndrome (DED), a multifactorial ocular surface disorder, presents significant treatment challenges in severe cases where conventional eye drops demonstrate limited efficacy. Current lacrimal occlusion strategies, while clinically valuable, are compromised by a device migration and sizing inaccuracies that undermine therapeutic reliability. To address these limitations, we engineered an innovative SwitchPlug hydrogel as a switchable punctal plug formed in situ from pre-assembled mPEG-PLGA nanoparticles under the morphological and thermal cues of the lacrimal canaliculus, which affords reversible punctal occlusion and broad-spectrum drug loading capacity. The SwitchPlug hydrogel exhibits rapid sol-gel transition at physiological canalicular temperature (∼37 °C), forming stable occlusions that significantly prolong tear retention while permitting gentle, cooling-induced liquefaction for atraumatic removal, a critical safety advantage over current plugs. Beyond its mechanical occlusion, this smart hydrogel functions as a versatile drug reservoir capable of sustained release across diverse therapeutics, including hydrophobic small molecules (e.g., cyclosporine A), hydrophilic compounds (e.g., dequafosil sodium), and macromolecular proteins (e.g., human epidermal growth factor). In both mouse and rabbit DED models, cyclosporine A-loaded SwitchPlug hydrogel (CsA@SwitchPlug) demonstrated superior therapeutic efficacy compared to commercial formulations, effectively restoring tear secretion, suppressing corneal inflammation, reducing epithelial apoptosis, and accelerating tissue repair. Comprehensive biosafety evaluation confirmed excellent ocular and systemic biocompatibility. This integrated platform represents a paradigm shift in DED management by simultaneously addressing three critical clinical needs, including prolonged ocular retention, customizable drug delivery, and reversible mechanical occlusion, offering new possibilities for personalized and combinatorial therapy of DED.