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

Author

Listed:
  • Ruiteng Song

    (Jinan University)

  • Yongqi Lin

    (Southern University of Science and Technology)

  • Min Zhang

    (Jinan University)

  • Zhen Liu

    (Jinan University)

  • Rui Zhang

    (Jinan University)

  • Jun Zhao

    (Jinan University)

  • Bin Li

    (Jinan University
    Southern University of Science and Technology)

Abstract

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.

Suggested Citation

  • Ruiteng Song & Yongqi Lin & Min Zhang & Zhen Liu & Rui Zhang & Jun Zhao & Bin Li, 2025. "Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63553-5
    DOI: 10.1038/s41467-025-63553-5
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    References listed on IDEAS

    as
    1. Zhen Liu & Jiacai Wu & Ning Wang & Yongqi Lin & Ruiteng Song & Min Zhang & Bin Li, 2025. "Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    2. Ling Zhao & Xiang-Jun Chen & Jie Zhu & Yi-Bo Xi & Xu Yang & Li-Dan Hu & Hong Ouyang & Sherrina H. Patel & Xin Jin & Danni Lin & Frances Wu & Ken Flagg & Huimin Cai & Gen Li & Guiqun Cao & Ying Lin & D, 2015. "Correction: Corrigendum: Lanosterol reverses protein aggregation in cataracts," Nature, Nature, vol. 526(7574), pages 595-595, October.
    3. Seula Shin & Hao Zhou & Chenxi He & Yanjun Wei & Yunfei Wang & Takashi Shingu & Ailiang Zeng & Shaobo Wang & Xin Zhou & Hongtao Li & Qiang Zhang & Qinling Mo & Jiafu Long & Fei Lan & Yiwen Chen & Jian, 2021. "Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    4. Patricia Boya, 2021. "Lipid dismantling of lens organelles for clear vision," Nature, Nature, vol. 592(7855), pages 509-510, April.
    5. Ling Zhao & Xiang-Jun Chen & Jie Zhu & Yi-Bo Xi & Xu Yang & Li-Dan Hu & Hong Ouyang & Sherrina H. Patel & Xin Jin & Danni Lin & Frances Wu & Ken Flagg & Huimin Cai & Gen Li & Guiqun Cao & Ying Lin & D, 2015. "Lanosterol reverses protein aggregation in cataracts," Nature, Nature, vol. 523(7562), pages 607-611, July.
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