Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS-CoV-2.
Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS-CoV-2.
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DOI：
10.1002/advs.202202556
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发表时间：
2022-12
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影响因子：
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严重急性呼吸综合征冠状病毒2（SARS-CoV-2）可导致人类致命的肺损伤。它的包膜上含有刺突蛋白，可与气道细胞上表达的人血管紧张素转换酶2（hACE 2）结合，使病毒进入并引起感染。hACE 2的可溶性形式结合SARS-CoV-2刺突蛋白，阻止病毒进入靶细胞，并改善肺损伤;然而，其短半衰期限制了治疗效用。在这里，合成的mRNA被工程化以编码hACE 2（hsACE 2）的可溶形式以防止病毒感染。一种新型脂质纳米颗粒（LNP）用于包装和递送mRNA到细胞中以产生hsACE 2蛋白。腹腔注射LNP将mRNA递送至肝细胞，导致循环hsACE 2的产生在2小时内开始并持续数天。吸入LNP导致肺转染和粘膜hsACE 2分泌到肺上皮细胞，这是SARS-CoV-2的主要进入部位和发病机制。此外，mRNA产生的hsACE 2与病毒刺突蛋白的受体结合结构域结合。最后，hsACE 2有效地抑制SARS-CoV-2及其假病毒感染宿主细胞。原理证明研究表明，基于mRNA的纳米治疗剂可以用于中和SARS-CoV-2，并为2019冠状病毒病（COVID-19）开辟新的治疗机会。编码人可溶性血管紧张素转换酶2（hsACE 2）的mRNA可能是通过抑制病毒进入来治疗SARS-CoV-2感染的治疗选择。脂质纳米颗粒通过将mRNA递送至肝脏和肺部，能够快速生成循环和粘膜hsACE 2蛋白。
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can cause lethal pulmonary damage in humans. It contains spike proteins on its envelope that bind to human angiotensin‐converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The soluble form of hACE2 binds SARS‐CoV‐2 spike protein, prevents viral entry into target cells, and ameliorates lung injury; however, its short half‐life limits therapeutic utilities. Here, synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. A novel lipid nanoparticle (LNP) is used for packaging and delivering mRNA to cells to produce hsACE2 proteins. Intravenously administered LNP delivers mRNA to hepatocytes, leading to the production of circulatory hsACE2 initiated within 2 h and sustained over several days. Inhaled LNP results in lung transfection and secretion of mucosal hsACE2 to lung epithelia, the primary site of entry and pathogenesis for SARS‐CoV‐2. Furthermore, mRNA‐generated hsACE2 binds to the receptor‐binding domain of the viral spike protein. Finally, hsACE2 effectively inhibits SARS‐CoV‐2 and its pseudoviruses from infecting host cells. The proof of principle study shows that mRNA‐based nanotherapeutics can be potentially deployed to neutralize SARS‐CoV‐2 and open new treatment opportunities for coronavirus disease 2019 (COVID‐19). A mRNA encoding human soluble angiotensin‐converting enzyme 2 (hsACE2) could be a therapeutic option to treat SARS‐CoV‐2 infection by inhibiting the virus entry. Lipid nanoparticles enable a rapid generation of circulating and mucosal hsACE2 protein by delivering the mRNA to the liver and lungs.
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影响因子：
6.6
作者：
Herrera M;Kim J;Eygeris Y;Jozic A;Sahay G
通讯作者：
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影响因子：
17.1
作者：
Kim, Jeonghwan;Jozic, Antony;Lin, Yuxin;Eygeris, Yulia;Bloom, Elissa;Tan, Xiaochen;Acosta, Christopher;MacDonald, Kelvin D.;Welsher, Kevin D.;Sahay, Gaurav
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DOI：
10.1007/s00432-007-0311-0
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3.6
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通讯作者：
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影响因子：
64.8
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影响因子：
82.9
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