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 () and Xue-Qing Zhang ()
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Xin Bai: Shanghai Jiao Tong University
Qijing Chen: Shanghai Jiao Tong University
Fengqiao Li: New Jersey Institute of Technology
Yilong Teng: Shanghai Jiao Tong University
Maoping Tang: Shanghai Jiao Tong University
Jia Huang: Shanghai Jiao Tong University
Xiaoyang Xu: New Jersey Institute of Technology
Xue-Qing Zhang: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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-HP08LOOP 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-HP08LOOP 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 HP08LOOP 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.

Date: 2024
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DOI: 10.1038/s41467-024-51056-8

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