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

ABSTRACT 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 NM P188 ‐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.