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 (H 2 O 2 ) and Fe 2+ levels. Numerous nanomaterials have been developed to co-deliver H 2 O 2 and Fe 2+ or their prodrugs into tumor cells, aiming to enhance hydroxyl radical (•OH) level via Fenton reaction. However, the •OH generation efficacy is frequently undermined by catalase (CAT) and ferritin in cytoplasm, which can respectively catalyze H 2 O 2 to H 2 O and oxidize Fe 2+ to Fe 3+ . 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 H 2 O 2 production and Fe 2+ release, and then generate a huge amount of •OH. Macromolecules cannot pass through the “window”, which prevents the undesirable catalysis of ferritin and CAT. In vitro and in vivo 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. A hollow nanofactory with dotted interior surface (HNDIS) was designed and constructed with the function of glucose-driven H 2 O 2 generation and self-supplied Fe 2+ generation in the hollow core of HNDIS, which can produce potent hydroxyl radical to combat drug-resistant large tumors.