Mo Zhang, Zihan Gao, Sheng Feng, Xun Wang, Huaiyu Wang, Chumeng Yang, Xiaolei Lin, Zhiqiang Xu, Nan Zhang, Yiyang Li, Haochen Tian, Ningyi Jin, Bin Yu, Pengfei Wang, Chang Li, Xianghui Yu
Emerging viruses such as SARS-CoV-2 and HIV-1 pose major challenges for traditional vaccines due to their rapid mutation and immune evasion. Here, we present a modular liposomal nanoparticle (LNP) vaccine platform integrating trimeric immunogens and synergistic adjuvants to induce broad and durable immunity. Using a self-assembled SARS-CoV-2 RBD trimer (RM) based on MTQ and Ni 2+ /His-tag coupling, antigens were directionally displayed on LNPs coloaded with QS-21, MPLA, and R848 adjuvants. This RM-LNP formulation enhanced antigen stability, lymph node targeting, and germinal center responses, eliciting high titers of broadly neutralizing antibodies and strong T and memory B cell immunity. The RM-LNP vaccine conferred potent neutralization against Omicron subvariants and protected hACE2 mice from Delta, BA.5, and XBB infection. Extension to HIV-1 vaccine design also demonstrated significant and broad neutralization against Tier 2 strains. This study offers a versatile nanovaccine strategy for combating highly mutable viruses.