Targeting the Hedgehog Signaling Pathway in the Retina Using Quercetin-Loaded Lipid Nanoparticles for Myopia Control

Purpose: Myopia is emerging as a major global health concern, with the prevalence increasing to nearly epidemic levels. Currently, its pathogenesis and treatment methods still must be further studied. This study aimed to explore the therapeutic efficacy of quercetin in myopia control and attempt to decipher the underlying mechanism. Methods: A quercetin-loaded liposome (QLS) delivery system was prepared by a thin-film dispersion method assisted with ultrasonication. Guinea pigs with form-deprivation myopia were used to demonstrate the therapeutic efficacy of QLSs. The retinas were collected to verify the underlying mechanisms through proteomics, digital capillary western blotting, and multicolor immunofluorescence staining. Furthermore, the interactions between quercetin and target proteins were verified through molecular docking. Finally, blood biochemical indexes and morphological changes in vital organs were compared to evaluate the biosafety of QLSs. Results: The obtained QLSs displayed a uniform size distribution with an average diameter of 274.06 ± 26.98 nm (polydispersity index [PDI] = 0.202) and a negative surface charge of -15.0 mV. Notably, liposomal formulation markedly enhanced the water solubility and bioavailability of quercetin, facilitating effective myopia control at low doses. QLSs exhibit a sustained release effect and excellent in vivo biosafety. Mechanistically, QLSs inhibited activation of the hedgehog signaling pathway, suppressing the elongation of axial length. Conclusions: QLSs could suppress experimental myopia progression by inhibiting the activation of hedgehog signaling pathway, offering a promising approach for preventing myopia. Translational Relevance: QLSs exhibited excellent aqueous solubility and bioavailability, enabling low-dose administration with significant efficacy, thereby presenting great prospects for clinical application.