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We explored the potential of two types of sorbitan ester nanoparticles (SENS) as novel tools for topical ocular drug delivery. The optimized SENS formulation (SENS-OPT) consisted of nanoparticles (NPs) of 170.5 nm, zeta potential +33.9 mV, and cyclosporine loading of 19.66%. After hyaluronic acid (HA) coating, the resulting SENS-OPT-HA NPs had a particle size of 177.6 nm and zeta potential of −20.6 mV. The NPs were stable during 3 months of storage at different temperatures and did not aggregate in the presence of protein-enriched simulated lacrimal fluid. There was no toxicity to cultured human corneal epithelial (HCE) cells when exposed to NPs up to 0.4% (w/v). Both NPs were effectively internalized by HCE cells through active mechanisms. Endocytosis of SENS-OPT NPs was caveolin-dependent whereas SENS-OPT-HA NP endocytosis was mediated by HA receptors. HA-receptor–mediated endocytosis may be responsible for the higher cellular uptake of SENS-OPT-HA NPs. After cyclosporine incorporation into the NPs, corneal penetration of this immunosuppressive drug by loaded SENS-OPT NPs was 1.3-fold higher than the commercial reference formulation Sandimmun®. For cyclosporine-loaded SENS-OPT-HA NPs, the penetration was 2.1-fold higher than for Sandimmun®. In ex vivo stimulated lymphocytes, both formulations demonstrated the same reduction in IL-2 levels as Sandimmun®.