Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy

Xin Bai; Qijing Chen; Fengqiao Li; Yilong Teng; Maoping Tang; Jia Huang; Xiaoyang Xu; Xue-Qing Zhang

doi:10.1038/s41467-024-51056-8

Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy

Nat Commun. 2024 Aug 10;15(1):6844. doi: 10.1038/s41467-024-51056-8.

Authors

Xin Bai^{1

2}, Qijing Chen^{1

2}, Fengqiao Li^{3

4}, Yilong Teng^{1

2}, Maoping Tang^{1

2}, Jia Huang^{1

2}, 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

Lipid nanoparticle-assisted mRNA inhalation therapy necessitates addressing challenges such as resistance to shear force damage, mucus penetration, cellular internalization, rapid lysosomal escape, and target protein expression. Here, we introduce the innovative "LOOP" platform with a four-step workflow to develop inhaled lipid nanoparticles specifically for pulmonary mRNA delivery. iLNP-HP08^LOOP featuring a high helper lipid ratio, acidic dialysis buffer, and excipient-assisted nebulization buffer, demonstrates exceptional stability and enhanced mRNA expression in the lungs. By incorporating mRNA encoding IL-11 single chain fragment variable (scFv), scFv@iLNP-HP08^LOOP effectively delivers and secretes IL-11 scFv to the lungs of male mice, significantly inhibiting fibrosis. This formulation surpasses both inhaled and intravenously injected IL-11 scFv in inhibiting fibroblast activation and extracellular matrix deposition. The HP08^LOOP system is also compatible with commercially available ALC0315 LNPs. Thus, the "LOOP" method presents a powerful platform for developing inhaled mRNA nanotherapeutics with potential for treating various respiratory diseases, including idiopathic pulmonary fibrosis.

MeSH terms

Administration, Inhalation
Animals
Disease Models, Animal
Humans
Idiopathic Pulmonary Fibrosis* / drug therapy
Idiopathic Pulmonary Fibrosis* / immunology
Lipids / chemistry
Liposomes
Lung / metabolism
Lung / pathology
Male
Mice
Mice, Inbred C57BL
Nanoparticles* / chemistry
RNA, Messenger* / administration & dosage
RNA, Messenger* / genetics
RNA, Messenger* / metabolism
Single-Chain Antibodies* / administration & dosage

Substances

RNA, Messenger
Lipid Nanoparticles
Single-Chain Antibodies
Lipids
Liposomes