NGF-preconditioned exosome-functionalized hydrogels promote comprehensive corneal repair after chemical injury

Abstract Corneal alkali burns are sight-threatening emergencies, and current therapies cannot adequately lead to comprehensive tissue repair. Engineered mesenchymal stem cell-derived exosomes (MSC-Exos) are emerging as potent cell-free agents that regulate cellular behavior and improve therapeutic effectiveness. Here, we preconditioned MSCs with recombinant human nerve growth factor (rhNGF) to yield modified exosomes (N-Exos) to enhance neurotrophic effects and promote innervated comprehensive corneal repair. In vitro, the N-Exos significantly maintained limbal stem cell stemness, promoted trigeminal ganglion cell activity, and attenuated inflammation. Mechanistically, these benefits were partially mediated by rhNGF-induced exosomal miRNAs that regulate the Wnt/β-catenin and cAMP/PKA signaling pathways. We further introduced a thermosensitive Pluronic F-127 hydrogel (PF-127) as a carrier for N-Exos in an eye drop formulation to achieve sustained release and prolonged bioavailability. In vivo, N-Exos-PF-127 eye drops resulted in the most extensive restoration of corneal morphology and function, as evidenced by the ability of this treatment to promote epithelial and limbal healing, repair corneal nerves, reduce inflammation, and suppress corneal stromal fibrosis and neovascularization. This study demonstrates a synergistic strategy for comprehensive corneal alkali burn repair and presents a novel cell-free regenerative approach for treating ocular surface diseases.