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

• Published in: Nature communications Vol. 15; no. 1; pp. 6844 - 18
• Main Authors: Bai, Xin, Chen, Qijing, Li, Fengqiao, Teng, Yilong, Tang, Maoping, Huang, Jia, Xu, Xiaoyang, Zhang, Xue-Qing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/152; 639/166/985; 692/699/1785; Administration, Inhalation; Animals; Antibodies; Buffers; Damage; Dialysis; Disease Models, Animal; Extracellular matrix; Fibrosis; Gene expression; Humanities and Social Sciences; Humans; Idiopathic Pulmonary Fibrosis - drug therapy; Idiopathic Pulmonary Fibrosis - immunology; Immunotherapy; Inhalation; Interleukin 11; Internalization; Lipids; Lipids - chemistry; Liposomes; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Male; Mice; Mice, Inbred C57BL; mRNA stability; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Penetration resistance; Pulmonary fibrosis; Respiration; Respiratory diseases; RNA, Messenger - administration & dosage; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Shear forces; Single-Chain Antibodies - administration & dosage; Therapy; Workflow
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51056-8

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. Inhaled lipid nanoparticles face several challenges when delivered to the lungs. Here, the authors show “LOOP”-optimized iLNP-HP08 LOOP could withstand shear damage generated during nebulization process and be used to develop mRNA-mediated antibody therapy for treating idiopathic pulmonary fibrosis.