Multivalent display of envelope protein domain III with Mi3 nanoparticles induces protective immunity against lethal Zika virus infection in mice

Xikui Sun; Huadong Jiang; Wenqiang Yu; Nana Wang; Zhengfeng Li; Junnan Lu; Xiaolu Xie; Liqiang Feng

doi:10.1016/j.virs.2025.12.012

February 2026

Citation: Xikui Sun, Huadong Jiang, Wenqiang Yu, Nana Wang, Zhengfeng Li, Junnan Lu, Xiaolu Xie, Liqiang Feng. Multivalent display of envelope protein domain III with Mi3 nanoparticles induces protective immunity against lethal Zika virus infection in mice .VIROLOGICA SINICA, 2026, 41(1) : 182-195. http://dx.doi.org/10.1016/j.virs.2025.12.012

Multivalent display of envelope protein domain III with Mi3 nanoparticles induces protective immunity against lethal Zika virus infection in mice

Xikui Sun ^a,b,c ,
Huadong Jiang ^b,d ,
Wenqiang Yu ^a,b ,
Nana Wang ^b ,
Zhengfeng Li ^b ,
Junnan Lu ^b ,
Xiaolu Xie ^e ,
Liqiang Feng ^{b,f,g
,,}

a. Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China;
b. China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
c. Guangzhou National Laboratory, Guangzhou 510320, China;
d. School of Life Science, University of Science and Technology of China, Hefei 230026, China;
e. Guangzhou Medical University, Guangzhou 511436, China;
f. Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
g. University of Chinese Academy of Sciences, Beijing 100049, China

Corresponding author: Liqiang Feng, feng_liqiang@gibh.ac.cn
Received Date: 23 June 2025
Accepted Date: 29 December 2025
Available online: 02 January 2026

Fund Project: The authors also thank the staff in the Animal Center and Analytical Instrumentation Core of GIBH for their technical assistance.

Abstract

Zika virus (ZIKV) infection is associated with severe neurological complications such as congenital microcephaly, yet no safe and effective vaccine is currently available. A critical challenge in ZIKV vaccine development arises from cross-reactive, non- or sub-neutralizing antibodies, which may enhance dengue virus (DENV) infection through antibody-dependent enhancement (ADE). Herein, we report a vaccine strategy utilizing Mi3 nanoparticles to display the envelope (E) protein domain III (EDIII) of ZIKV, which induces protective immunity against ZIKV infection in murine models. Compared to an EDIII subunit vaccine, the Mi3-EDIII nanoparticle vaccine elicited significantly higher antibody responses and stronger cell-mediated immune responses. In C57BL/6 mice, maternal immunization with Mi3-EDIII protected the neonates against ZIKV-caused symptoms, including body weight loss, neurological abnormalities, retardation of brain development, and mortality. In interferon-α/β receptor knockout (Ifnar1-/-) C57BL/6 mice, Mi3-EDIII immunization conferred effective protection against lethal ZIKV challenge. Notably, unlike ZIKV convalescent sera, Mi3-EDIII immune sera did not enhance DENV infection in human chronic myelogenous leukemia K562 cells, suggesting the absence of ADE-prone antibody induction. Our results demonstrate that Mi3-EDIII is a promising vaccine candidate against ZIKV infection and warrants further development.
- Zika virus (ZIKV)
- , EDIII
- , Nanoparticle vaccine
- , Antibody-dependent enhancement

Electronic Supplementary Material

10.1016j.virs.2025.12.012-ESM.docx
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