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

Jia Huang; Xin Bai; William Stewart; Xiaoyang Xu; Xue-Qing Zhang

doi:10.1038/s41467-025-61114-4

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

Nat Commun. 2025 Jul 1;16(1):6013. doi: 10.1038/s41467-025-61114-4.

Authors

Jia Huang^{1

2}, Xin Bai^{1

2}, William Stewart^{3

4}, Xiaoyang Xu^{5

6}, Xue-Qing Zhang^{7

8}

Affiliations

¹ Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
² National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, USA.
⁴ Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA.
⁵ Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, USA. xiaoyang.xu@njit.edu.
⁶ Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA. xiaoyang.xu@njit.edu.
⁷ Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China. xueqingzhang@sjtu.edu.cn.
⁸ National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China. xueqingzhang@sjtu.edu.cn.

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 (iLNP_BUD5) to deliver mRNA encoding a thymic stromal lymphopoietin nanobody (mnbTSLP) for the treatment of steroid-resistant asthma. Upon nebulization, mnbTSLP-iLNP_BUD5 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.

MeSH terms

Administration, Inhalation
Animals
Asthma* / drug therapy
Asthma* / immunology
Budesonide* / administration & dosage
Budesonide* / pharmacology
Cytokines* / genetics
Cytokines* / immunology
Disease Models, Animal
Drug Resistance / drug effects
Female
Humans
Lipids / chemistry
Liposomes
Lung / drug effects
Lung / pathology
Mice
Mice, Inbred BALB C
Nanoparticles* / administration & dosage
Nanoparticles* / chemistry
RNA, Messenger* / administration & dosage
RNA, Messenger* / genetics
Single-Domain Antibodies* / administration & dosage
Single-Domain Antibodies* / genetics
Thymic Stromal Lymphopoietin

Substances

Budesonide
RNA, Messenger
Cytokines
Thymic Stromal Lymphopoietin
Single-Domain Antibodies
Lipid Nanoparticles
Lipids
TSLP protein, mouse
Liposomes