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Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats
Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats
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Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats
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Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats
Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats

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Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats
Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats
Journal Article

Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats

2025
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Overview
Cataract caused by crystallin aggregation is the leading cause of vision impairment and blindness globally. The only available treatment option so far is surgery. In this study, we leverage lipid nanoparticles (LNPs)-formulated mRNA encoding human lanosterol synthase (hLSS) to elevate lanosterol levels in the lens as a potential anti-cataract therapy. hLSS mRNA delivered with aromatized LNPs can be avidly taken up and translated into hLSS proteins in mammalian cells. mRNA formulations administered via intravitreal, subconjunctival, intracameral, or subretinal injection in rats display distinct kinetics and bio-distribution profiles, among which intracameral injection achieves sustained and selective protein expression in the lens. In comparison to clinically used LNPs, aromatized LNPs show more than seven-fold higher mRNA delivery potency in rats upon intracameral injection, without inducing significant ocular lesions. Furthermore, ocular delivery of hLSS mRNA-loaded formulations leads to elevated levels of hLSS proteins and lanosterol within the lens and a remarkable improvement in cataract symptoms in two rat models of cataract. Collectively, topical delivery of hLSS mRNA-LNPs to the eyes offers a potential strategy to reduce intracellular aggregation of crystallins and ameliorate cataract development. Surgery is currently the only treatment option for cataract. Here, the authors report on ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase as a potential anti-cataract therapy, which ameliorates cataract development in two rat cataract models.