Lung-Targeted Lipid Nanoparticle-Delivered siUSP33 Attenuates SARS-CoV-2 Replication and Virulence by Promoting Envelope Degradation

Zhou, Yuzheng1; Liao, Yujie2; Fan, Lujie1,3; Wei, Xiafei1; Huang, Qiang1; Yang, Chuwei1; Feng, Wei1; Wu, Yezi1; Gao, Xiang1; Shen, Xiaotong1; Zhou, Jian1; Xia, Zanxian2,4,5; Zhang, Zheng1,6

2024-09-01

10.1002/advs.202406211

ADVANCED SCIENCE   影响因子和分区

2198-3844

["As a structural protein of SARS-CoV-2, the envelope (E) protein not only plays a key role in the formation of viral particles, but also forms ion channels and has pathogenic functions, including triggering cell death and inflammatory responses. The stability of E proteins is controlled by the host ubiquitin-proteasome system. By screening human deubiquitinases, it is found that ubiquitin-specific protease 33 (USP33) can enhance the stability of E proteins depending on its deubiquitinase activity, thereby promoting viral replication. In the absence of USP33, E proteins are rapidly degraded, leading to a reduced viral load and inflammation. Using lipid nanoparticle (LNP) encapsulation of siUSP33 by adjusting the lipid components (ionizable cationic lipids), siUSP33 is successfully delivered to mouse lung tissues, rapidly reducing USP33 expression in the lungs and maintaining knockdown for at least 14 days, effectively suppressing viral replication and virulence. This method of delivery allows efficient targeting of the lungs and a response to acute infections without long-term USP33 deficiency. This research, based on the deubiquitination mechanism of USP33 on the E protein, demonstrates that LNP-mediated siRNA delivery targeting USP33 plays a role in antiviral and anti-inflammatory responses, offering a novel strategy for the prevention and treatment of SARS-CoV-2.","The envelope (E) protein of SARS-CoV-2 hijacks the deubiquitinase ubiquitin-specific protease 33 (USP33) in host cells to cleave off K48-typed polyubiquitin chains and antagonize E3 ubiquitin ligase RNF5-mediated degradation. Lipid nanoparticles target the delivery of siUSP33 to the lungs, effectively knock down USP33, and promote the proteasome-dependent degradation of the E protein, inhibiting viral replication and attenuating virulence. image"]

deubiquitinase envelope (E) lipid nanoparticles SARS-CoV-2 USP33

SCI

英语

第一 ; 通讯

National Natural Science Foundation of China["82402592","92369109","82072293","U21A20384"] ; Major Project of Guangzhou National Laboratory[GZNL2024A01014] ; Chinese Academy of Medical Sciences Clinical and Translational Medicine Research Project[2022-I2M-CT-B-113] ; National Science Fund for Distinguished Young Scholars[82025022] ; Guangdong Science and Technology Plan Project, construction of high-level biosafety laboratories[2021B1212030010] ; Guangdong Basic and Applied Basic Research Foundation["2024A1515012490","2023A1515111136"] ; Shenzhen Science and Technology Program["JCYJ20220818103017036","RCBS20231211090709013"] ; null[2021YFC2300103]

Chemistry ; Science & Technology - Other Topics ; Materials Science

Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary

WOS:001316106600001

WILEY

Web of Science

1.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Affiliated Hosp 2, Inst Hepatol,Natl Clin Res Ctr Infect Dis,Sch Med, Shenzhen 518112, Peoples R China
2.Cent South Univ, Sch Life Sci, Dept Cell Biol, Changsha 410083, Peoples R China
3.Guangzhou Lab, Guangzhou 510700, Peoples R China
4.Cent South Univ, Sch Life Sci, Hunan Key Lab Anim Models Human Dis, Hunan Key Lab Med Genet, Changsha 410013, Peoples R China
5.Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha 410013, Peoples R China
6.Chinese Acad Med Sci, Shenzhen Res Ctr Communicable Dis Diag & Treatment, Shenzhen 518112, Peoples R China

Zhou, Yuzheng,Liao, Yujie,Fan, Lujie,et al. Lung-Targeted Lipid Nanoparticle-Delivered siUSP33 Attenuates SARS-CoV-2 Replication and Virulence by Promoting Envelope Degradation[J]. ADVANCED SCIENCE,2024.

Zhou, Yuzheng.,Liao, Yujie.,Fan, Lujie.,Wei, Xiafei.,Huang, Qiang.,...&Zhang, Zheng.(2024).Lung-Targeted Lipid Nanoparticle-Delivered siUSP33 Attenuates SARS-CoV-2 Replication and Virulence by Promoting Envelope Degradation.ADVANCED SCIENCE.

Zhou, Yuzheng,et al."Lung-Targeted Lipid Nanoparticle-Delivered siUSP33 Attenuates SARS-CoV-2 Replication and Virulence by Promoting Envelope Degradation".ADVANCED SCIENCE (2024).