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

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.