Conjugation‐Free Multilamellar Protein‐Lipid Hybrid Vesicles for Multifaceted Immune Responses

Abstract Various lipid‐based nanocarriers have been developed for the co‐delivery of protein antigens with immunological adjuvants. However, their in vivo potency in vaccine delivery is limited by structural instability, which causes off‐target delivery and low cross‐presentation efficacies. Recent works employ covalent cross‐linking to stabilize the lipid nanostructures, though the immunogenicity and side effects of chemically modified protein antigens and lipids can cause a long‐lasting safety issue. Here robust “conjugation‐free” multilamellar protein antigen‐lipid hybrid nanovesicles (MPLVs) are introduced through the antigen‐mediated self‐assembly of unilamellar lipid vesicles for the co‐delivery of protein antigens and immunologic adjuvants. The nanocarriers coated with monophosphoryl lipid A and hyaluronic acids elicit highly increase antigen‐specific immune responses in vitro and in vivo. The MPLVs increase the generation of immunological surface markers and cytokines in mouse‐derived bone‐marrow dendritic cells compared to soluble antigens with adjuvants. Besides, the vaccination of mice with the MPLVs significantly increase the production of anti‐antigen antibody and interferon‐gamma via the activation of CD4 + and CD8 + T cells, respectively. These findings suggest that MPLVs can serve as a promising nanovaccine delivery platform for efficient antigen cross‐presentation through the efficient co‐delivery of protein antigens with adjuvants.