Vitreous humor–mimetic liposomes enable effective gene delivery to the eye via intravitreal injection

Inherited retinal disorders such as Norrie disease lack effective therapies, largely owing to the challenges of delivering genes to retinal tissues via intravitreal injection. The efficacy of gene delivery is constrained by physical impediments, including the inner limiting membrane and the viscoelastic characteristics of the vitreous humor. In this study, we present the development of vitreous humor–mimetic liposomes (VMLs), which have been shown to facilitate efficient retinal gene delivery by enhancing biocompatibility and tissue absorption. The VMLs were engineered by reproducing the lipidomic composition of the native vitreous, as identified through liquid chromatography–mass spectrometry analysis. The subretinal injection of VMLs was conducted to assess the efficiency of gene expression delivery by VMLs. Notably, VML #3 demonstrated a 1.3-fold enhanced GFP transfection compared to conventional nanoparticle, Lipofectamine 2000. Following intravitreal administration, VML #3 facilitated efficient delivery of pGFP–NDP (Norrie disease protein) plasmids and restored retinal vascularization in both Ndp-hemizygous and oxygen-induced retinopathy mouse models. The findings demonstrate the potential of tissue-inspired nanocarriers as effective platforms for enhancing intraocular delivery, suggesting a clinically applicable strategy for the treatment of inherited retinal diseases, including Norrie disease. Intravitreal (IVT) injection is one of the most promising methods for delivering drugs into the eyes, but it is highly hindered by the high viscosity of the vitreous. Here, vitreous humor–mimetic liposomes (VML) enable efficient delivery of pGFP-NDP plasmid into the eyes. IVT injection of pGFP-NDP-loaded VML showed neovascularization in oxygen-induced retinopathy mouse models, showing therapeutic efficacy of VMLs. • Vitreous humor–mimetic liposomes (VML) enhance pGFP transfection efficiency via intravitreal injection • VML show lower toxicity and higher pGFP transfection efficiency in vivo • pGFP-NDP-encapsulating VML successfully restored vascularization in Ndp-hemizygous and oxygen induced retinopathy (OIR) mouse models.