A multi-scale nanoparticle delivery system enhances neutralizing antibody responses in subunit vaccines

Current subunit vaccines targeting infectious diseases, such as AIDS, face significant challenges in effectively activating immune responses, particularly in inducing broadly neutralizing antibodies (bNAbs). Nanoparticles (NPs) offer an effective delivery platform for subunit vaccines, providing distinct advantages including antigen stabilization and targeted delivery. In this study, we developed an innovative multi-scale NP delivery system using amino-modified mesoporous silica NPs (MSNs) with a 13 nm pore size. This system was designed to load and present HIV-1 native-like envelope (Env) proteins, UFO-BG, which were pre-assembled on ferritin nanocages (referred to as UFO-BG-FR). The UFO-BG-FR@MSN enabled highly stable and dense array presentation of Env proteins, while effectively exposing their neutralizing epitopes. Compared to free Env protein UFO-BG, UFO-BG-FR@MSN enhanced multivalent interactions with antigen-presenting cells, thereby facilitating the antigen uptake and activation effects of lymph node dendritic cells and B cells. This also promoted the robust activation of follicular helper T cells and germinal center B cells in lymph nodes. In guinea pigs, UFO-BG-FR@MSN induced broader and more sustained neutralizing antibody (NAb) responses, targeting multiple bNAb epitopes on the Env. These results highlight the importance of multi-scale NPs in addressing the insufficient immunogenicity of subunit vaccines. Our findings offer a promising delivery strategy for designing vaccines against infectious diseases caused by highly mutated viruses.