Phenotype-Based Selection of Cyclosporine A Formulations in Dry Eye Disease: Integration of Molecular, Rheological, and Clinical Outcomes

PURPOSE: Cyclosporine A (CsA) is widely used for dry eye disease (DED), yet therapeutic outcomes vary substantially across available formulations. Growing evidence suggests that formulation properties, rather than CsA concentration alone, determine ocular surface bioavailability and clinical response. This study compared the molecular, rheological, and clinical characteristics of CsA formulations to establish a phenotype-based therapeutic selection strategy for DED management. METHODS: Human conjunctival epithelial cells under hyperosmotic stress were treated with 0.05% CsA nanoemulsion, 0.1% CsA cationic emulsion, or 0.05% CsA anionic emulsion. Expression of inflammatory cytokines (MMP-9 and TNF-α) was quantified by real-time PCR. Rheological assessments characterized viscosity and shear-thinning behavior. Clinically, 63 patients with moderate-to-severe DED were treated with either 0.05% CsA nanoemulsion or 0.1% CsA cationic emulsion for 4 months and were evaluated using OSDI, Schirmer I, tear break-up time, and ocular surface staining. RESULTS: The 0.05% CsA nanoemulsion demonstrated greater cytokine suppression and exhibited higher viscosity with greater resistance to shear, corresponding to greater improvement in Schirmer I. And 0.1% CsA cationic CsA produced a more pronounced improvement in tear break-up time, consistent with enhanced tear film spreading. Both treatments improved symptoms without serious adverse events. CONCLUSIONS: The therapeutic efficacy of topical CsA is primarily determined by formulation-tear film interactions. The 0.05% CsA nanoemulsion is more appropriate for aqueous-deficient DED, where prolonged ocular residence supports tear volume recovery, whereas 0.1% CsA cationic emulsion is better suited for tear-film instability or evaporative DED, where improved spreading enhances tear film stability. These results support phenotype-based selection of CsA formulations to optimize treatment precision.