Amorphous layered double hydroxide-based nano-enzyme eye drops against dry eye disease by inhibiting mitochondrial damage and pyroptosis

Chronic inflammation serves as a prominent contributor to the progression of dry eye disease (DED). Reactive oxygen species (ROS) and the downstream NLRP3 inflammasome mediate pyroptosis, which induces the inflammatory response by releasing several inflammatory factors. Therefore, targeting pyroptosis represents a promising therapeutic strategy for controlling inflammation in DED. Herein, we report the amorphous layered double hydroxide (a-LDH)-based nano-enzyme eye drops (Needs) for DED. The a-LDH exhibits superior hydroxyl radicals (·OH) and superoxide anions (·O₂^-) scavenging capabilities, which are 1.77 times and 1.20 times that of the crystalline ZnCuAl-LDH, and 3.38 times and 1.43 times that of conventional CeO₂, respectively. The augmented performance stems from the synergistic effect of Cu⁺/Cu²⁺ redox couples facilitating electron shuttling for radical disproportionation and oxygen vacancies serving as both preferential adsorption sites and active catalytic domains for ROS breakdown. More importantly, the a-LDH efficiently scavenges excess ROS, inhibits NLRP3/Caspase-1/GSDMD signaling axis-mediated pyroptosis and N-GSDMD-induced mitochondrial damage. In vivo assays indicate that the Needs reduce the expression of pro-inflammatory cytokines, reverse corneal epithelial defects, restore goblet cell density, and tear secretion in mice DED model. Our findings provide valuable insights into the underlying mechanisms and potential therapeutic strategies of LDH-based nano-enzymes for DED.