Silica-coated papillomavirus-based nanoparticles: a shielded scaffold for HIV-1 vaccines

The development of a safe, effective, and accessible human immunodeficiency virus 1 (HIV-1) vaccine remains a global priority, and nanoparticles (NPs) have emerged as a promising platform for vaccine delivery. However, the efficacy of protein-based NP vaccines is often limited by pre-existing immunity against scaffold components. In this study, we developed a novel HIV-1 vaccine platform by converting self-assembling human papillomavirus (HPV) L1 virus-like particles (VLPs) into immune-stealth biomaterials for focused antigen delivery. Encapsulation of VLPs within a silica shell provided both immune shielding and a surface for site-specific antigen conjugation. The resulting L1-SiO₂ NPs were covalently functionalized with HIV-1 Env trimers (L1-SiO₂-Env) and characterized for their physicochemical properties and immunogenicity. In vivo, the silica coating effectively masked L1-specific B cell epitopes, reduced anti-scaffold IgG responses and enhanced Env-specific antibody production in mice pre-immunized against HPV. This synthetic strategy offers a versatile platform for overcoming scaffold-directed immunity in nanoparticle vaccines.