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Budesonide-incorporated inhalable lipid nanoparticles for antiTSLP nanobody mRNA delivery to treat steroid-resistant asthma

Jia Huang, Xin Bai, William Stewart, Xiaoyang Xu () and Xue-Qing Zhang ()
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Jia Huang: Shanghai Jiao Tong University
Xin Bai: Shanghai Jiao Tong University
William Stewart: New Jersey Institute of Technology
Xiaoyang Xu: New Jersey Institute of Technology
Xue-Qing Zhang: Shanghai Jiao Tong University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Asthma exacerbations and steroid resistance occur due to disruption of the airway epithelium, limiting the effectiveness of corticosteroids. Although monoclonal antibodies have progressively emerged as adjunctive therapy for steroid-resistant asthma, there remains a clinical need for targeted anti-inflammatory therapies with better efficacy and fewer off-target effects. Here, we propose the ASCEND (Alternative Steroids Co-delivering with mRNA Encoding Nanobodies) approach, which utilizes inhalable lipid nanoparticles formulated with budesonide (iLNPBUD5) to deliver mRNA encoding a thymic stromal lymphopoietin nanobody (mnbTSLP) for the treatment of steroid-resistant asthma. Upon nebulization, mnbTSLP-iLNPBUD5 targets the lungs, enhancing antiTSLP nanobody production while delivering budesonide. This combined therapy reduces airway inflammation, remodeling, and hyperresponsiveness in murine models. Additionally, mnbTSLP restores the sensitivity of steroid-resistant asthmatic mice to budesonide by inhibiting key inflammatory pathways. The ASCEND approach shows superior effects compared to corticosteroid or antiTSLP antibody treatments, offering a promising strategy for steroid-resistant asthma and potentially other respiratory diseases.

Date: 2025
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DOI: 10.1038/s41467-025-61114-4

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