Ectoine-Loaded Solid Lipid Nanoparticles Enhance the Protection of Lacrimal Glands and Corneal Tissues in Dry Eye Disease Through Modulating NF-κB Mediated Signaling Pathway

Abstract

Dry eye disease (DED) is a multifactorial disorder associated with tear film instability, inflammation, and ocular surface damage. This study aimed to develop and evaluate Ectoine-loaded solid lipid nanoparticles (Ect-SLNs) as a novel ocular drug delivery system to improve corneal penetration, retention, and therapeutic efficacy. Ect-SLNs were formulated using a Box-Behnken design and characterized for particle size, polydispersity index, zeta potential, and encapsulation efficiency. In vitro release kinetics were assessed. Ex vivo ocular retention studies were performed using bovine cornea. In vivo therapeutic efficacy was evaluated in a scopolamine-induced rat model of DED, with histological and immunohistochemical analyses of corneal and lacrimal gland tissues. The optimized Ect-SLN formulation exhibited a mean particle size, zeta potential and entrapment efficiency of 241.3 +/- 32.1 nm, -15.76 +/- -4.14 mV, and 32.84 + 3.15 % respectively. In vitro studies demonstrated that Ect-SLNs showed sustained release following Higuchi kinetics (r(2) = 0.991). Ex vivo studies confirmed 1.6-fold higher corneal retention compared to Ectoine solution. Animal studies showed that Ect-SLNs significantly improved glandular and corneal morphology, epithelial keratinization, apoptotic (Bax, Caspase-3) and pro-inflammatory (TNF-alpha, IL-1 beta) markers through NF-kappa B signaling pathway (p < 0.05). In addition, Ect-SLN formulation significantly inhibited the upregulated EGFR in corneal tissue, which is an important hallmark of neovascularization (p < 0.05). Ect-SLNs provided superior therapeutic benefits over conventional Ectoine solution by enhancing bioavailability, prolonging ocular residence, and modulating inflammatory and apoptotic responses. These findings suggest that Ect-SLNs constitute a promising nanocarrier platform for the clinical management of dry eye disease.