Charge-assisted stabilization of lipid nanoparticles enables inhaled mRNA delivery for mucosal vaccination

Shuai Liu, Yixing Wen, Xinzhu Shan, Xinghuan Ma, Chen Yang, Xingdi Cheng, Yuanyuan Zhao, Jingjiao Li, Shiwei Mi, Haonan Huo, Wei Li, Ziqiong Jiang, Yijia Li, Jiaqi Lin, Lei Miao and Xueguang Lu ()
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Shuai Liu: Chinese Academy of Sciences
Yixing Wen: Chinese Academy of Sciences
Xinzhu Shan: Peking University
Xinghuan Ma: Dalian University of Technology
Chen Yang: Chinese Academy of Sciences
Xingdi Cheng: Chinese Academy of Sciences
Yuanyuan Zhao: Chinese Academy of Sciences
Jingjiao Li: Chinese Academy of Sciences
Shiwei Mi: Chinese Academy of Sciences
Haonan Huo: Chinese Academy of Sciences
Wei Li: Chinese Academy of Sciences
Ziqiong Jiang: Peking University
Yijia Li: Peking University
Jiaqi Lin: Dalian University of Technology
Lei Miao: Peking University
Xueguang Lu: Chinese Academy of Sciences

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

Abstract: Abstract Inhaled delivery of messenger RNA (mRNA) using lipid nanoparticle (LNP) holds immense promise for treating pulmonary diseases or serving as a mucosal vaccine. However, the unsatisfactory delivery efficacy caused by the disintegration and aggregation of LNP during nebulization represents a major obstacle. To address this, we develop a charge-assisted stabilization (CAS) strategy aimed at inducing electrostatic repulsions among LNPs to enhance their colloidal stability. By optimizing the surface charges using a peptide-lipid conjugate, the leading CAS-LNP demonstrates exceptional stability during nebulization, resulting in efficient pulmonary mRNA delivery in mouse, dog, and pig. Inhaled CAS-LNP primarily transfect dendritic cells, triggering robust mucosal and systemic immune responses. We demonstrate the efficacy of inhaled CAS-LNP as a vaccine for SARS-CoV-2 Omicron variant and as a cancer vaccine to inhibit lung metastasis. Our findings illustrate the design principles of nebulized LNPs, paving the way of developing inhaled mRNA vaccines and therapeutics.

Date: 2024
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DOI: 10.1038/s41467-024-53914-x

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