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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\u2010stemmed spherical nucleic acids (SNAs) coupled with immunostimulatory CpG strands, denoted as Fe\u2010CpG, are synthesized to explore the immune activation mechanisms. It is shown that Fe\u2010CpG efficiently entered cells and simultaneously activated TLR7, TLR8, and TLR9 within the endosome, triggering the downstream IRF5, IRF7, and NF\u2010\u03baB pathways, rather than engaging in the STING pathway. The IONP core of Fe\u2010CpG is essential for the activation of TLR7\u2010 and TLR8\u2010mediated pathways. When used as an adjuvant with a COVID\u201019 subunit vaccine, Fe\u2010CpG outperforms both gold nanoparticle\u2010based SNA and the clinically approved aluminum adjuvant. These results reveal how IONPs activate innate immune pathways and highlight the potential of Fe\u2010CpG as a potent nano\u2010adjuvant.<\/jats:p>","DOI":"10.1002\/smll.202508378","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T07:21:36Z","timestamp":1756538496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Iron Oxide Nanoparticles Activate Innate Immunity Through Toll\u2010Like Receptors and Cooperate with CpG as a Potent Nano\u2010Adjuvant"],"prefix":"10.1002","volume":"21","author":[{"given":"Chen","family":"Yang","sequence":"first","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences CAS Key Laboratory of Colloid Interface and Chemical Thermodynamics Institute of Chemistry Chinese Academy of Sciences  Beijing 100190 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 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