Hybrid nanogel system of quercetin-loaded squalene NLCs with zinc-HA network for dry eye syndrome.

Dry eye syndrome (DES) is a multifactorial ocular surface disorder characterized by tear film instability, inflammation, and ocular irritation. Conventional therapies are often limited by rapid precorneal elimination, low bioavailability, and frequent administration. To overcome these limitations, quercetin-loaded squalene linoleic acid nanostructured lipid carriers were incorporated into a ZnSO₄ cross-linked hyaluronic acid nanogel (QS-NLCs-Zn-HA nanogel), developed as a potential therapeutic system for DES management. The nanogel was prepared via ionic cross-linking between cationic ZnSO₄ and anionic hyaluronic acid and characterized for pH, spreadability, viscosity, and FT-IR spectra to ensure optimal ocular performance. In vitro drug release studies revealed 97.36 ± 1.22% release and 33.68 ± 1.03% corneal permeation within 12 h. The formulation exhibited enhanced antioxidant and anti-inflammatory activity, by reducing IL-1, TNF-α, and IL-6 levels compared with controls. Furthermore, cellular internalization and wound-healing capabilities were markedly improved. The HET-CAM assay and in vivo ocular irritation studies (modified Draize test) confirmed the formulation's ocular safety and effectiveness. Pharmacokinetic evaluation demonstrated approximately 2.5-fold longer half-life (t₁/₂), 3.17-fold higher area under the curve (AUC), and 2.98-fold greater mean residence time in tears compared with pure quercetin. Overall, the developed QS-NLCs-Zn-HA nanogel exhibited superior bioavailability, sustained release, and enhanced therapeutic potential, suggesting its promise as an effective and safe formulation for the treatment of dry eye syndrome.