Protein corona-driven nanovaccines improve antigen intracellular release and immunotherapy efficacy

During vaccine delivery in vivo, the vaccine carrier dynamically adsorbs the surrounding proteins or biomacromolecules to form a protein corona layer, which determines the physiological and therapeutic responses of the vaccine. Although the importance of the protein corona effect in drug delivery is widely accepted, understanding of the rational use of the protein corona to improve antigen controlled release is still sparse. Here, we constructed a protein corona-driven nanovaccine (PCNV), which has the dual effects of resisting the protein corona-induced antigen extracellular release and promoting protein corona-triggered antigen cytosolic release under reductive conditions. Specifically, the nanovaccine was formulated via the assembly of fluorinated dendrigraft-poly-lysine and cleavable antigen-CpG conjugate. Before entering antigen-presenting cells (APCs), the anchoring effect of CpG was used to avoid the dissociation of antigens from the carrier even under the protein corona effect. While nanovaccine enters the APCs, the intracellular reducing conditions can induce a break in the disulfide bond between CpG and antigen. Notably, at the same time, the intracellular protein corona effect triggers antigen release from the carrier and achieves efficient antigen presentation. In addition, the PCNV produced a significant prophylactic and therapeutic antitumor response in the mouse model. Therefore, the rational use of the protein corona effect provides an effective strategy for vaccine delivery.