Tetrahedral DNA‐Based Functional MicroRNA‐21 Delivery System: Application to Corneal Epithelial Wound Healing

Abstract Corneal injury occurs frequently which may lead to serious visual impairment. Rapid and efficient re‐epithelialization after corneal epithelial injury is the key issue for maintaining corneal homeostasis. Among various treatment strategies, microRNA (miR)‐based therapy shows great potential. However, structural limitations of miRNAs hinder its biomedical functionality. Nucleic acid nanotechnology is an appealing candidate for gene delivery because of its flexible modification and excellent biocompatibility. Herein, modified 3D tetrahedral framework nucleic acids (tFNAs) utilized as gene carriers for miR‐21 delivery are constructed. TFNAs‐miR‐21 (T‐21) shows great enzymatic resistance in extracellular environment and payload delivery into human corneal epithelial cells (HCECs) via clathrin‐mediated endocytosis. T‐21 facilitates proliferation and migration in HCECs via activating PI3K/AKT and ERK1/2 signaling pathways in vitro. In vivo studies, T‐21 can be internalized by corneal epithelium in mice. In the mice corneal scratch model, T‐21 ophthalmic solutions used as eye drops show no apparent side effects on the ocular surface histologically and exert great potential in accelerating corneal wound healing. These findings demonstrate that modified tFNAs are promising candidates for miRNA delivery for corneal wound healing. The convenient administration and great biocompatibility of tetrahedral DNA nanoparticles highlight its potential as gene transporter in solving ocular problems.