Ion‑Responsive in situ Gel of Quercetin‑Loaded PEGylated Liposomes for Anti‑inflammatory Treatment of Dry Eye Disease.

BACKGROUND

Dry eye disease (DED) is a global health burden with limited effective and safe treatments. Quercetin (Qu) possesses potent anti-inflammatory and antioxidant activities, but its poor solubility and short half-life restrict ophthalmic use.

METHODS

Qu‑loaded PEGylated liposomes (Qu‑PL) were prepared by thin‑film hydration and incorporated into gellan gum to form an ion‑responsive in situ gel (Qu‑PL‑ISG). The formulation was characterized for particle size (PS), zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE), short-stability, in vitro release, cytotoxicity, ocular irritation, mucoadhesion, ocular surface retention, pharmacokinetics, and therapeutic efficacy in a BAC‑induced DED mouse model. Network pharmacology and molecular docking were used to generate testable hypotheses on possible mechanisms of Qu in DED.

RESULTS

Qu‑PL‑ISG had a PS of 173.33 ± 1.27 nm, a ZP of -46.87 ± 0.95 mV, and an EE of 88.85 ± 1.41%. It released 46% of Qu over 72 h and remained stable for 21 days at 4 °C, with no cytotoxicity or irritation. Compared with Qu‑PL, Qu‑PL‑ISG exhibited higher mucoadhesive force (3783.5 ± 125.2 vs. 1986.2 ± 145.7 dyne/cm2) and longer ocular surface retention (45 vs. 20 min). Ocular bioavailability (AUC0‑1 80) in cornea, conjunctiva, and tears increased 2.79-, 1.47- and 1.44-fold, respectively. In DED mice, 0.2% Qu‑PL-ISG restored tear secretion, reduced corneal staining, repaired epithelial thickness, increased goblet cell density, and lowered corneal IL-1β and TNF-α levels, with efficacy comparable to 0.05% cyclosporine A. Network pharmacology and molecular docking were used as computational tools to predict that Qu may act on DED through multi‑target interactions (TNF, NF‑κB, STAT3, IL-1β, AKT1, IL-6, Src) and pathways (IL-17, PI3K-Akt, TNF signaling), though these findings require experimental validation.

CONCLUSION

Qu‑PL‑ISG is a safe, ion‑activated in situ gel that significantly enhances Qu bioavailability and anti‑inflammatory efficacy, showing promise for DED treatment.