Lactic acid responsive sequential production of hydrogen peroxide and consumption of glutathione for enhanced ferroptosis tumor therapy.

[Display omitted] • A concept of "natural product-induced and lactate depletion-enhanced ferroptosis" strategy is proposed for promoting the occurrence of ferroptosis. • The engineered lactic acid responsive natural product delivery system presents unique cascade enzymatic/Fenton catalytic performance for distinctive ferroptosis-based anticancer therapy. • The strategy integrating natural product and tumor-specific GPX4 deactivation presents an effective ferroptosis inducing strategy. • This work might provide new insight for realizing effective ferroptosis-based tumor treatment. Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H 2 O 2) into hydroxyl radicals (•OH) by Ir3+-mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H 2 O 2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H 2 O 2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy. [ABSTRACT FROM AUTHOR]