Nanomicelles self-assembled using cyclosporine A-hyaluronic acid conjugates for dry eye disease treatment.

Dry eye disease is a chronic inflammatory disorder of the ocular surface in which tear film instability and hyperosmolarity perpetuate a self-sustaining cycle of epithelial damage and inflammation; however, the therapeutic efficacy of topical cyclosporine A (CsA), a mainstay of treatment, is severely limited by rapid tear clearance and poor ocular bioavailability. Here, we developed a CsA-modified hyaluronic acid conjugate (HA-CsA) that spontaneously self-assembled into nanoparticles for topical DED therapy. HA-CsA nanomicelles (HCN) were synthesized through thiol-maleimide coupling and exhibited good dispersibility and stability in physiological media, with tear-compatible pH and osmolality. Under hyperosmotic stress, CD44 expression was upregulated in human corneal epithelial cells, and R6G-labeled HCN showed markedly enhanced cellular uptake compared with free R6G, indicating improved epithelial delivery. Functionally, HCN demonstrated greater cytocompatibility than free CsA and more effectively suppressed hyperosmotic stress-induced expression of IL-1β, IL-6, IL-8, TNF-α, and MMP-9. In a desiccating-stress mouse model of DED, topically administered HCN significantly improved corneal epithelial integrity, tear secretion and goblet cell survival while broadly attenuating inflammatory gene expression, macrophage activation and epithelial apoptosis, outperforming free cyclosporine A across all parameters. This conjugation-driven nanoplatform integrates tear film stabilization, targeted epithelial delivery and sustained local immunomodulation into a single, well-defined formulation, providing a promising translational strategy for interrupting the vicious inflammatory cycle that drives dry eye disease.