Framework Nucleic Acids Nanoplatform Regulating Cellular Stemness and Oxidative Microenvironment for Synergistic Treatment of Ocular Surface Disorders

Abstract Corneal alkali burns (CAB) represent an ophthalmic emergency and pose a significant challenge due to extremely severe complications and poor prognosis. The CAB‐induced vicious cycle that involves oxidative stress, sustained inflammation, limbal stem cell deficiency, and delayed epithelial healing critically disrupts ocular surface homeostasis, rendering conventional corticosteroid monotherapy insufficient. Herein, this study proposes a synergistic treatment approach regulating cellular stemness and oxidative microenvironment against CAB. The framework nucleic acids (FNAs) are developed to load L‐ascorbic acid 2‐phosphate (AA2P) with high loading capacity. The resulting FNAs‐AA2P significantly inhibits the oxidative stress, mitochondrial membrane potential abnormality, and apoptosis of corneal epithelial progenitor cells (TKE2) under alkali conditions in vitro. Furthermore, FNAs‐AA2P regulates the expression of critical markers (e.g., K14, P63, and SOX2), associated with enhanced proliferation and stemness of TKE2 cells. Therapeutically, the multifunctional FNAs‐AA2P exhibits superior therapeutic efficacy in the CAB mouse model by accelerating epithelium recovery, mitigating corneal opacity, and suppressing corneal neovascularization. This synergistic treatment approach not only represents a promising candidate for CAB but also offers valuable insights for the management of other multifactorial disorders.