Appropriate Size of Fe₃O₄ Nanoparticles for Cancer Therapy by Ferroptosis

Iron oxide nanoparticles can induce cell death due to the ferroptosis mechanism, showing a great potential for cancer therapy. Here, we synthesized different-sized iron oxide nanoparticles (2-100 nm) to investigate their antitumor effect and toxicity mechanism. It was found that ultrasmall nanoparticles (< ∼5 nm) could accumulate in nucleus and were more efficient in triggering the generation of ^•OH than larger nanoparticles due to the quicker release of Fe²⁺, thus exhibiting more remarkable cytotoxicity. Nevertheless, 10 nm iron oxide nanoparticles group displayed the best antitumor effect in vivo. We studied the in vivo and intratumoral biodistribution of the nanoparticles and found that the therapeutic effects were related to both the tumoral accumulation and intratumoral distribution of nanoparticles. This work indicates the appropriate size of Fe₃O₄ NPs for cancer treatment and illustrates the possible factors that influence the therapeutic effect, suggesting the great potential of iron oxide in clinical application.