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

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

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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