Abstract
The incidence of dry eye disease (DED) has been increasing annually worldwide, creating an urgent need for new therapies. Due to the multifactorial mechanism underlying DED, traditional medications focused on decreasing ocular surface inflammation have been unable to address all the harmful factors and fail to achieve a complete clinical cure. Ferroptosis, a new form of programmed cell death characterized by lipid peroxidation, has become a pivotal contributor to dry eye oxidative stress-driven pathology. Therefore, therapeutic targeting of ferroptosis may be an attractive option for dry eye management. Herein, a sialic acid-targeting peptide-modified liposome loaded with Cyclosporine A (CsA), a typical anti-inflammatory drug, and Ferrostatin-1 (Fer-1), a selective ferroptosis inhibitor, is developed termed as CF@SNPs, for combing and sustaining DED treatment. This multifunctional liposomal encapsulation demonstrates excellent aqueous solubility; moreover, the sialic acid-targeting peptide prolongs ocular surface retention, further enhancing therapeutic efficacy. The CF@SNPs treatment comprehensively alleviates DED symptoms, including improving corneal defects, augmenting goblet cell count, and restoring tear secretion. Specifically, CF@SNPs attenuate dry eye pathology by suppressing p53-SLC7A11-GSH-dependent ferroptosis and TNF-α-associated inflammatory cascades, accompanied by favorable biocompatibility in vivo. These results underscore the promising potential of this superior nano-formulation for DED pharmacotherapy.