Fluoropolymer-Mediated Delivery of a Dual TSHR/IGF1R-Targeting CRISPR-Cas9 System for Localized Therapy in Thyroid-Associated Ophthalmopathy

  • Adv Mater. 2026 Feb;38(11):e11078. doi: 10.1002/adma.202511078.
Mingsu Shi  1  2  3  4 ,  Panting Yu  5 ,  Lingyun Liu  1  2  3  4 ,  Jinwei Cheng  1  2  3  4 ,  Runyi Shao  1  2  3  4 ,  Ye Sun  1  2  3  4 ,  Jia Lv  5 ,  Yuhan Li  5 ,  Zihan Zheng  1  2  3  4 ,  Jian Yu  1  2  3  4 ,  Binbin Xu  1  2  3  4 ,  Lu Gan  1  2  3  4 ,  Yu Liang  1  2  3  4 ,  Yihan Zhang  1  2  3  4 ,  Yanxi Fang  1  2  3  4 ,  Weiai Shen  1  2  3  4 ,  Jinhai Huang  1  2  3  4 ,  Xiangjia Zhu  1  2  3  4 ,  Jiaxu Hong  1  2  3  4 ,  Ruiqi Ma  1  2  3  4 ,  Lianqun Wu  1  2  3  4 ,  Yiyun Cheng  5 ,  Chen Zhao  1  2  3  4  6
Affiliations
  • 1. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
  • 2. Key laboratory of Myopia and Related Eye Diseases, NHC, Shanghai, China.
  • 3. Key laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 4. Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.
  • 5. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
  • 6. Xiamen Eye Center of Xiamen University, Xiamen, China.
PMID: 41486850 DOI: 10.1002/adma.202511078
Abstract

Thyroid-associated ophthalmopathy (TAO), a vision-threatening and disfiguring autoimmune orbital disorder, remains a therapeutic challenge due to the lack of therapies with orbital specificity, sustained efficacy, and minimal side effects. Herein, we present G4F7-CRISPR, a fluoropolymer-based CRISPR-Cas9 delivery platform engineered for localized and efficient disruption of thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF1R), two key mediators of TAO pathogenesis. G4F7-CRISPR achieved high insertion/deletion frequencies in primary orbital fibroblasts (Tshr: 37.2%; Igf1r: 42.8%) and mature adipocytes (Tshr: 22.4%; Igf1r: 24.3%), and maintained robust editing efficiency in orbital adipose tissue of TAO mouse models (Tshr: 30.7%; Igf1r: 32.4%). In both TAO mouse models and 3D human orbital organoids, dual-gene editing of Tshr and Igf1r via G4F7-CRISPR significantly suppressed orbital adipogenesis, inflammation, and fibrosis, demonstrating superior therapeutic efficacy over either single-gene approaches. Comprehensive off-target analyses in both TAO mouse models and orbital organoids revealed minimal off-target activity. Furthermore, G4F7-CRISPR exhibited excellent short- and long-term ocular and systemic safety in TAO mouse models. Notably, it outperformed teprotumumab-the FDA-approved therapy for TAO-in both therapeutic efficacy and safety, highlighting its potential clinical advantages. Collectively, these findings highlight the translational promise of G4F7-CRISPR as a safe, precise, and clinically viable gene therapy for TAO.

Keywords
CRISPR‐Cas9; fluoropolymer; insulin‐like growth factor 1 receptor; thyroid‐associated ophthalmopathy; thyroid‐stimulating hormone receptor.
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