Retinal diseases, including age-related macular degeneration (AMD), are a major cause of blindness. Efficient delivery of therapeutic genes to retinal cells to treat retinal disease is a formidable challenge. In this study, we developed a core-shell nanoplatform composed of a core and two external layers for targeted delivery of the gene to the retina. The inner core was composed of amino acid-functionalized dendrimers and a nuclear localization signal (NLS) for DNA complexation, nuclear transport and efficient transfection. The inner core was coated in a lipid bilayer that comprised pH-sensitive lipids as the inner shell layer. Hyaluronic acid (HA)-1,2-dioleoylphosphatidylethanolamine (DOPE) as the outermost shell layer was used for retinal cell targeting. This core-shell nanoplatform was developed so that the mobility in the vitreous body of these negatively charged carriers would not be affected by their surface charge, allowing diffusion into the retina, uptake into the retinal cells via CD44-mediated internalization, and finally transport into the nucleus by the NLS. The designed nanoparticles showed safety both in vitro and in vivo and inhibited the expression of VEGF under hypoxia-mimicking conditions. In vitro angiogenesis assays exhibited significant inhibitory effects on cell migration and tube formation. The in vivo assays indicated that this nanoplatform could be delivered to the retina. Taken together, this nanoplatform has the potential to transfer gene material into the retina for the treatment of retinal diseases, including AMD.Copyright © 2021. Published by Elsevier Ltd.
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