DNA-Engineered Modular Nanovaccines Featuring Precise Topology for Enhanced Immunogenicity

Yanfei Qu; Dawei Wang; Yunlong Zhang; Fengyun Shen; Binghui Xia; Qin Xu; Qisheng Wang; Huating Kong; Ying Zhu; Lihua Wang; Itamar Willner; Xiurong Yang; Chunhai Fan; Lele Sun

doi:10.1002/adma.202500577

DNA-Engineered Modular Nanovaccines Featuring Precise Topology for Enhanced Immunogenicity

Adv Mater. 2025 May 15:e2500577. doi: 10.1002/adma.202500577. Online ahead of print.

Authors

Yanfei Qu¹, Dawei Wang², Yunlong Zhang¹, Fengyun Shen¹, Binghui Xia², Qin Xu³, Qisheng Wang³, Huating Kong³, Ying Zhu¹, Lihua Wang¹, Itamar Willner⁴, Xiurong Yang⁵, Chunhai Fan⁵, Lele Sun¹

Affiliations

¹ Institute of Materiobiology, Department of Chemistry, College of Science, Shanghai University, Shanghai, 200444, China.
² Department of Microbiology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
³ Shanghai Synchrotron Radiation Facility (SSRF), Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China.
⁴ Institute of Chemistry, The Minerva Center for Bio-hybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
⁵ School of Chemistry and Chemical Engineering, New Cornerstone Science Laboratory, Frontiers Science Center for Transformative Molecules, Zhang jiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.

PMID: 40371439
DOI: 10.1002/adma.202500577

Abstract

Multivalent display of antigens can boost subunit vaccine immunogenicity. However, owing to the inherent difficulty in programmatically controlling the topology of multivalent antigens, its impact on antigen immunogenicity remains elusive. In this study, DNA-mediated modular precision assembly is employed to organize SARS-CoV-2 receptor-binding domains (RBDs) with different topological connections while preserving their epitopes. It is found that branching-connected RBDs induced significantly higher IgG titers than linear-connected RBDs at higher antigen valency (≥4). This increase in IgG response is associated with stronger B cell proliferation, likely due to enhanced antigen-receptor synergistic interactions leading to enhanced B cell receptor signaling. Branching-connected RBDs also provided superior humoral immunity in mice and stronger protection in SARS-CoV-2-infected hamsters compared to adjuvanted RBD. This work highlights the role of antigen topology in vaccine design and offers a universal modular platform for producing more effective subunit vaccines.

Keywords: DNA self‐assembly; antigens; humoral immunity; subunit vaccines; topology.

Abstract

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