Hollow nanofactory with dotted interior surface produces potent hydroxyl radical to combat drug-resistant large tumors

Ferroptosis, a novel form of programmed cell death, is highly dependent on intracellular hydrogen peroxide (H₂O₂) and Fe²⁺ levels. Numerous nanomaterials have been developed to co-deliver H₂O₂ and Fe²⁺ or their prodrugs into tumor cells, aiming to enhance hydroxyl radical (•OH) level <i>via</i> Fenton reaction. However, the •OH generation efficacy is frequently undermined by catalase (CAT) and ferritin in cytoplasm, which can respectively catalyze H₂O₂ to H₂O and oxidize Fe²⁺ to Fe³⁺. Herein, we designed and constructed a hollow nanofactory with dotted interior surface (HNDIS), which is composed of hollow mesoporous iron oxide nanoparticle (HMION, "house" of the nanofactory) with mesoporous channels ("window" of the nanofactory), and ultrasmall gold nanoparticles (AuNP) on the interior surface ("machine" of the nanofactory). The unique "window" allows pass for glucose to co-work with AuNP and HMION to drive H₂O₂ production and Fe²⁺ release, and then generate a huge amount of •OH. Macromolecules cannot pass through the "window", which prevents the undesirable catalysis of ferritin and CAT. <i>In vitro</i> and <i>in vivo</i> experiments have demonstrated potent •OH production ability and powerful tumor suppression efficacy based on ferroptosis for HNDIS, offering a promising pathway to combat drug-resistant large tumors.