Designer Solid Self‐Emulsifying Nanovaccines Enable Dual Modulation of Dendritic Cells and T Cells for Potent Antitumor Immunity

Abstract Peptide‐based cancer vaccines offer favorable safety and stability profiles but are limited by rapid clearance and poor immunogenicity. Here, a ≈20 nm solid self‐emulsifying (SSE) nanovaccine platform that co‐delivers peptide antigens and an oligonucleotide adjuvant containing the 5'‐C‐phosphate‐G‐3' (CpG) motif is reported. This formulation elicits T‐cell responses 40 fold higher than those of conventional emulsified vaccines and even achieves complete tumor regression at low doses. Apolipoprotein E (ApoE) adsorbed on SSE vaccines enhances lymph node targeting and dendritic cell internalization. Furthermore, SSE is internalized by T cells and promotes lipid raft formation, thereby further sensitizing T cells to activation. These findings reveal a dual mechanism of immune regulation through the simultaneous engagement of dendritic cells and T cells. The SSE platform offers a clinically translatable strategy for potent cancer immunotherapy and provides mechanistic insights into nanoparticle–immune cell interactions that may guide the design of next‐generation nanovaccines.