A hollow mesoporous iron oxide nanoparticle to strengthen Fenton reaction and weaken antioxidant defense systems for high efficacy tumor ferroptosis therapy

[Display omitted] •A hollow mesoporous iron oxide nanoparticle (HMSPION) was prepared.•HMSPION has a hollow core of ∼ 100 nm and mesoporous shell of ∼ 40 nm.•HMSPION is a great drug delivery system with a wide application prospect.•LAP@HMSPION@Zn can strengthen Fenton reaction in tumors.•LAP@HMSPION@Zn can weaken antioxidant defense systems in tumors. Traditional drug delivery system (DDS) such as hollow mesoporous organosilica nanoparticle (HMON) can achieve efficient delivery of ferroptosis-inducing agents for tumor therapy due to its high drug loading content (DLC), but is limited by their slow degradation and the uselessness of their silicon-based compounds. In this study, a novel hollow mesoporous superparamagnetic iron oxide nanoparticle (HMSPION) was developed with 100 nm of hollow core and 40 nm of mesoporous shell with a high DLC (up to 22.9 %) of β-Lapachone (LAP), doxorubicin (DOX), sorafenib (SFN) and/or Zn2+. Furthermore, we propose a new strategy to strengthen Fenton reaction and weaken antioxidant defense systems in tumors by co-loading Zn2+ and LAP into HMSPION to generate LAP@HMSPION@Zn. Specifically, i) LAP@HMSPION@Zn is degraded into Fe2+/3+, Zn2+, and LAP in acidic tumor microenvironment. ii) LAP catalyzes O2 to be superoxide anion radical (O2•−) and Zn2+ raises the O2•− production in mitochondria. iii) The O2•− can be catalyzed into hydrogen peroxide (H2O2) via superoxide dismutase. iv) H2O2 and the released Fe2+ accelerate the Fenton reaction, generating highly toxic hydroxyl radical (•OH). v) The Fe3+ consumes GSH and LAP downregulates GSH level by NADPH consumption, thereby relieving the antioxidant defense systems in tumor cells.