Iron Oxide Nanoparticles Activate Innate Immunity Through Toll‐Like Receptors and Cooperate with CpG as a Potent Nano‐Adjuvant

Iron oxide nanoparticles (IONPs) have wide biomedical applications and are initially considered with minimal immunogenicity. Recent studies reveal that IONPs can activate the immune system through reactive oxygen species (ROS) or interferon regulatory factor (IRF) pathways. However, the exact mechanism remains unclear. To address this question, IONP‐stemmed spherical nucleic acids (SNAs) coupled with immunostimulatory CpG strands, denoted as Fe‐CpG, are synthesized to explore the immune activation mechanisms. It is shown that Fe‐CpG efficiently entered cells and simultaneously activated TLR7, TLR8, and TLR9 within the endosome, triggering the downstream IRF5, IRF7, and NF‐κB pathways, rather than engaging in the STING pathway. The IONP core of Fe‐CpG is essential for the activation of TLR7‐ and TLR8‐mediated pathways. When used as an adjuvant with a COVID‐19 subunit vaccine, Fe‐CpG outperforms both gold nanoparticle‐based SNA and the clinically approved aluminum adjuvant. These results reveal how IONPs activate innate immune pathways and highlight the potential of Fe‐CpG as a potent nano‐adjuvant.