Two‐Pronged Intracellular Co‐Delivery of Antigen and Adjuvant for Synergistic Cancer Immunotherapy

Abstract Nanovaccines have emerged as promising alternatives or complements to conventional cancer treatments. Despite the progresses, specific co‐delivery of antigen and adjuvant to their corresponding intracellular destinations for maximizing the activation of antitumor immune responses remains a challenge. Herein, a lipid‐coated iron oxide nanoparticle is delivered as nanovaccine (IONP‐C/O@LP) that can co‐deliver peptide antigen and adjuvant (CpG DNA) into cytosol and lysosomes of dendritic cells (DCs) through both membrane fusion and endosome‐mediated endocytosis. Such two‐pronged cellular uptake pattern enables IONP‐C/O@LP to synergistically activate immature DCs. Iron oxide nanoparticle also exhibits adjuvant effects by generating intracellular reactive oxygen species, which further promotes DC maturation. IONP‐C/O@LP accumulated in the DCs of draining lymph nodes effectively increases the antigen‐specific T cells in both tumor and spleen, inhibits tumor growth, and improves animal survival. Moreover, it is demonstrated that this nanovaccine is a general platform of delivering clinically relevant peptide antigens derived from human papilloma virus 16 to trigger antigen‐specific immune responses in vivo.