Biomimetic Multimodal Evaluation Reveals Enhanced Efficacy and Safety of Cyclosporine A Nanomicelles (CycloNex) for Advanced Dry Eye Management.

Dry eye disease (DED), which affects over 30% of the global population, demands advanced therapeutic strategies to overcome ocular bioavailability challenges. We developed nanomicelles (RH40-P188/RH40-P407, CycloNex) for enhanced cyclosporine A (CsA) delivery through innovative biological validation platforms. The 15-nm micelles demonstrated exceptional stability (3 months at 25°C) and deep tissue penetration (50 µm in 3D corneal spheroids), outperforming Cequa by 2.3-fold in ex vivo rabbit corneal accumulation. A breakthrough microfluidic-integrated 3D total corneal model revealed 82% prolonged ocular retention vs. Cequa, while our hyperosmotic cell platform showed 55% greater reactive oxygen species reduction and 44% lower TNF-α expression. In vivo studies confirmed NMP188-CsA's superior bioavailability, and corneal repair was completed within 14 days in mice with benzalkonium chloride-induced dry eye. These findings, validated through six complementary biological models-including HET-CAM irritation scoring (0.89 vs. Cequa's 1.34)-establish a new paradigm for ocular nanotherapeutic evaluation while demonstrating clinically translatable advantages over current standards.