Acidity‐Biodegradable Iridium‐Coordinated Nanosheets for Amplified Ferroptotic Cell Death Through Multiple Regulatory Pathways

Abstract

Ferroptosis‐based treatment strategies display the potential to suppress some malignant tumors with intrinsic apoptosis resistance. However, current related cancer treatments are still hampered by insufficient intracellular reactive oxygen species (ROS) levels and Fe2+ contents, posing considerable challenges for their clinical translation. Herein, an intracellular acid‐biodegradable iridium‐coordinated nanosheets (Ir‐Hemin) with sonodynamic therapy (SDT) properties to effectively induce ferroptosis in tumor cells through multiple regulatory pathways are proposed. Under ultrasound (US) irradiation, Ir‐Hemin nanosheets act as nanosonosensitizers to effectively generate ROS, subsequently causing the accumulation of lipid peroxides (LPO) and inducing ferroptotic cell death. Furthermore, these Ir‐Hemin nanosheets decompose quickly to release hemin and Ir(IV), which deplete intracellular glutathione (GSH) to deactivate the enzyme glutathione peroxidase 4 (GPX4) and initiate the ferroptosis pathway. Specifically, the released hemin enables heme oxygenase 1 (HO‐1) upregulation for endogenous ferrous ion supplementation, which compensates for the toxicity concerns brought about by the large uptake of exogenous iron. Surprisingly, Ir‐Hemin nanosheets exhibit high tumor accumulation and trigger effective ferroptosis for tumor therapy. These Ir‐Hemin nanosheets display pronounced synergistic anticancer efficacy under US stimulation both in vitro and in vivo, providing a strong rationale for the application of ferroptosis in cancer treatment.

Ternary heterostructure-driven photoinduced electron-hole separation enhanced oxidative stress for triple-negative breast cancer therapy

“…In order to ascertain that AZGH NPs can produce ROS efficiently, DCFH-DA known as a fluorescent redox probe was utilized to detect ROS in cell experiments. As a cell permeability tracer, DCFH-DA can be oxidized instantaneously upon interaction with ROS to yield extremely high flourescent 2’, 7’-dichlorofluorescein (DCF) molecules [ 50 ]. Upon exposure to NIR irradiation, AZ NPs incited a discernible level of ROS production.…”

Folate-targeted iridium complexes amplify photodynamic therapy efficacy through ferroptosis

“…The capacity of 1 O 2 to oxidize GSH (a crucial antioxidant molecule present in the extracellular milieu) can lead to a decline in its levels and an elevation in oxidative stress. 41 The generation of oxidative stress triggers iron-dependent cell death, also known as ferroptosis. During this process, 1 O 2 reacts with lipids to produce lipid peroxides causing membrane damage and cell death.…”

Recent Progress in Ferroptosis Induced Tumor Cell Death by Anti‐tumor Metallic complexes

“…The change of Ir IV to Ir III lead to decreased level of GSH and GPX4. [32] Nie et al [33] reported IrO 2 based nanocluster, HSAÀ Ce6À IrO 2 , namely HCIr. When subjected to ultrasonic condition, large amounts of 1 O 2 were produced, high accumulation of LPO and subsequently ferroptosis happened.…”

“…When presented to acidic TME, it degraded to Hemin and Ir IV , where Hemin could upregulate HO‐1 and intracellular Fe 2+ level to promote ferroptosis. The change of Ir IV to Ir III lead to decreased level of GSH and GPX4 [32] . Nie et al [33] .…”