Cyclic catalysis of intratumor Fe initiated by a hollow mesoporous iron sesquioxide nanoparticle for ferroptosis therapy of large tumors.

Numerous nanoparticles have been utilized to deliver Fe for tumor ferroptosis therapy, which can be readily converted to Fevia Fenton reactions to generate hydroxyl radical (•OH). However, the ferroptosis therapeutic efficacy of large tumors is limited due to the slow conversion of Fe to Fevia Fenton reactions. Herein, a strategy of intratumor Fe cyclic catalysis is proposed for ferroptosis therapy of large tumors, which was realized based on our newly developed hollow mesoporous iron sesquioxide nanoparticle (HMISN). Cisplatin (CDDP) and Gd-poly(acrylic acid) macrochelates (GP) were loaded into the hollow core of HMISN, whose surface was modified by laccase (LAC). Fe, CDDP, GP, and LAC can be gradually released from CDDP@GP@HMISN@LAC in the acidic tumor microenvironment. The intratumor O can be catalyzed into superoxide anion (O•) by LAC, and the intratumor NADPH oxidases can be activated by CDDP to generate O•. The O• can react with Fe to generate Fe, and raise HO level via the superoxide dismutase. The generated Fe and HO can be fast converted into Fe and •OH via Fenton reactions. The cyclic catalysis of intratumor Fe initiated by CDDP@GP@HMISN@LAC can be used for ferroptosis therapy of large tumors.