“…The germinal center (GC) is the center of B cell clonal expansion, somatic hypermutation, affinity-based selection, and the production of high-affinity antibodies. , However, satisfactory antigen delivery to lymph node (LN) and activation of APCs (dendritic cells (DCs), macrophages, and B cells) remain major concerns for protein subunit-based vaccines. Presenting protein antigens on the surface of nanoparticles (NPs) is a promising approach, as NPs can more effectively transport and accumulate in distinct compartments of the LN, and a multivalent antigen display on the surface of NPs can more effectively engage and cross-link low-affinity B cell receptors (BCRs) on naive B cells and even use B cells instead of DCs for antigen presentation to initiate the T cell response, thus enabling GC formation. − NPs can now be roughly divided into two categories that include self-assembling protein NPs such as ferritin, heat shock protein, or the E2 subunit of the pyruvate dehydrogenase complex and synthetic NPs such as lipid-based, inorganic, and polymeric NPs . Both types of NPs exhibit enhanced immunogenicity relative to soluble antigens that protect against several diseases, including AIDS, influenza, and COVID-19. − However, these nanoparticle-based vaccines typically need to be immunized with other adjuvants such as AddaVax, ISCOMATRIX, and Sigma Adjuvant System (SAS) adjuvant, etc., − and the mechanism underlying the induction of GC responses by these adjuvants and nanovaccines remains poorly understood.…”