2. Academic Validation
  3. Targeted Knockdown of Epithelial Estrogen Receptor α to Mitigate Ferroptosis and Epithelial-Mesenchymal Transition in Eosinophilic Asthma

Targeted Knockdown of Epithelial Estrogen Receptor α to Mitigate Ferroptosis and Epithelial-Mesenchymal Transition in Eosinophilic Asthma

  • ACS Nano. 2025 Jun 10;19(22):21105-21117. doi: 10.1021/acsnano.5c05314.
Weiyun Zhang 1 2,  Shengding Zhang 3 4 5,  Lijuan Hua 3 6,  Wenxue Bai 3 6,  Lu Qin 3 6,  Junqing Yue 3 6,  Dongyuan Wang 3 6,  Mengyao Guo 3 6,  Xuezhao Wang 3 6,  Harald Renz 7 8,  Skevaki Chrysanthi 7 8,  Gang Wang 9,  Zhihong Chen 10,  Haifeng Dong 2,  Min Xie 3 6
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.
  • 2 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, P. R. China.
  • 3 Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.
  • 4 Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 1519 Dongyue Avenue, Nanchang 330006, P. R. China.
  • 5 Department of Pulmonary and Critical Care Medicine, National Regional Center for Respiratory Medicine, Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang 330000, P. R. China.
  • 6 Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan 430030, P. R. China.
  • 7 Institute of Laboratory Medicine, Philipps University Marburg, Marburg 35392, Germany.
  • 8 Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Marburg 35392, Germany.
  • 9 Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
  • 10 Department of Respiratory and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai 200433, P. R. China.
PMID: 40424612 DOI: 10.1021/acsnano.5c05314
Abstract

Estrogen receptor α (ERα) is involved with the hyperresponsiveness and airway remodeling in asthma, but developing therapies targeting ERα remains challenging due to its multifaceted roles in different cell types and the poor efficacy of systemic ERα intervention in asthma. Previously, we uncovered the association of increased ERα expression in airway epithelial cells with poor pulmonary function and epithelial-mesenchymal transition (EMT) in asthma patients. This study further investigated the association of ERα expression with the Ferroptosis and EMT levels in a cohort of eosinophilic asthma (EA) patients as well as in an eosinophil-epithelial coculture cell model. By loading small interfering RNA (siRNA) into a mesoporous silica nanoparticle (MSN) and then coating the extracted bronchial epithelial cytomembrane (CM), a bronchial epithelial CM home-targeting nanoplatform (siRNA@MSN@CM) was constructed to selectively decrease the ERα expression in bronchial epithelial cells. The targeting effect of bronchial epithelial cells was confirmed in vitro and in vivo, demonstrating the successful targeted knockdown of ERα expression. Silencing ERα in epithelial cells effectively prevented Ferroptosis and EMT induced by coculturing with ferroptotic eosinophils. Targeted intervention of epithelium ERα with intratracheal delivery of siRNA(ERα)@MSN@CM nanoparticle significantly reduced the levels of Ferroptosis in bronchial epithelial cells, airway inflammation, and airway remodeling in asthmatic mouse models. This study introduces an innovative nanomaterial for targeted drug delivery to epithelial cells and underscores the potential of targeted knockdown ERα in bronchial epithelial cells as a therapeutic strategy for asthma treatment.

Keywords

biomimetic membrane; eosinophilic asthma; epithelial–mesenchymal transition; estrogen receptor α; ferroptosis; siRNA nanomedicine.

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