A lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection

Wanbo Tai, Kai Yang, Yubin Liu, Ruofan Li, Shengyong Feng, Benjie Chai, Xinyu Zhuang, Shaolong Qi, Huicheng Shi, Zhida Liu, Jiaqi Lei, Enhao Ma, Weixiao Wang, Chongyu Tian, Ting Le, Jinyong Wang, Yunfeng Chen, Mingyao Tian (), Ye Xiang (), Guocan Yu () and Gong Cheng ()
Additional contact information
Wanbo Tai: Tsinghua University
Kai Yang: Tsinghua University
Yubin Liu: Tsinghua University
Ruofan Li: Tsinghua University
Shengyong Feng: Tsinghua University
Benjie Chai: Tsinghua University
Xinyu Zhuang: Chinese Academy of Agricultural Sciences
Shaolong Qi: Tsinghua University
Huicheng Shi: Tsinghua University
Zhida Liu: Shanxi Academy of Advanced Research and Innovation
Jiaqi Lei: Tsinghua University
Enhao Ma: Tsinghua University
Weixiao Wang: Tsinghua University
Chongyu Tian: Tsinghua University
Ting Le: Tsinghua University
Jinyong Wang: Shenzhen Bay Laboratory
Yunfeng Chen: Shenzhen Bay Laboratory
Mingyao Tian: Chinese Academy of Agricultural Sciences
Ye Xiang: Tsinghua University
Guocan Yu: Tsinghua University
Gong Cheng: Tsinghua University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by intravenous administration and the short half-life period of antibodies in the lungs by intranasal or aerosolized immunization, mRNA encoding broadly neutralizing antibodies with lung-targeting capability can perfectly provide high-titer antibodies in lungs to prevent the SARS-CoV-2 infection. Here, we firstly identify a human monoclonal antibody, 8-9D, with broad neutralizing potency against SARS-CoV-2 variants. The neutralization mechanism of this antibody is explained by the structural characteristics of 8-9D Fabs in complex with the Omicron BA.5 spike. In addition, we evaluate the efficacy of 8-9D using a safe and robust mRNA delivery platform and compare the performance of 8-9D when its mRNA is and is not selectively delivered to the lungs. The lung-selective delivery of the 8-9D mRNA enables the expression of neutralizing antibodies in the lungs which blocks the invasion of the virus, thus effectively protecting female K18-hACE2 transgenic mice from challenge with the Beta or Omicron BA.1 variant. Our work underscores the potential application of lung-selective mRNA antibodies in the prevention and treatment of infections caused by circulating SARS-CoV-2 variants.

Date: 2023
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DOI: 10.1038/s41467-023-43798-8

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