Cyclic catalysis of intratumor Fe^3+/2+ initiated by a hollow mesoporous iron sesquioxide nanoparticle for ferroptosis therapy of large tumors.

Abstract

Numerous nanoparticles have been utilized to deliver Fe²⁺ for tumor ferroptosis therapy, which can be readily converted to Fe³⁺via Fenton reactions to generate hydroxyl radical (•OH). However, the ferroptosis therapeutic efficacy of large tumors is limited due to the slow conversion of Fe³⁺ to Fe²⁺via Fenton reactions. Herein, a strategy of intratumor Fe^3+/2+ 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). Fe³⁺, CDDP, GP, and LAC can be gradually released from CDDP@GP@HMISN@LAC in the acidic tumor microenvironment. The intratumor O₂ can be catalyzed into superoxide anion (O₂•^-) by LAC, and the intratumor NADPH oxidases can be activated by CDDP to generate O₂•^-. The O₂•^- can react with Fe³⁺ to generate Fe²⁺, and raise H₂O₂ level via the superoxide dismutase. The generated Fe²⁺ and H₂O₂ can be fast converted into Fe³⁺ and •OH via Fenton reactions. The cyclic catalysis of intratumor Fe^3+/2+ initiated by CDDP@GP@HMISN@LAC can be used for ferroptosis therapy of large tumors.