Glutathione Consumption Research Articles

Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.

BackgroundPlatinum‐based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown.MethodsPlatinum drug‐sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain‐of‐function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay.ResultsThe derivative brain metastatic subpopulations (PC9‐BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM.ConclusionsCollectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.

Arsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy

The modulation of intracellular reactive oxygen species (ROS) levels is crucial for cellular homeostasis and determination of cellular fate. A sublethal level of ROS sustains cell proliferation, differentiation and promotes tumor metastasis, while a drastic ROS burst directly induces apoptosis. Herein, surface-oxidized arsenene nanosheets (As/AsxOy NSs) with type II heterojunction are fabricated with efficient ·O2− and 1O2 production and glutathione consumption through prolonging the lifetime of photo-excited electron-hole pairs. Moreover, the portion of AsxOy with oxygen vacancies not only catalyzes a Fenton-like reaction, generating ·OH and O2 from H2O2, but also inactivates main anti-oxidants to cut off the “retreat routes” of ROS. After polydopamine (PDA) and cancer cell membrane (M) coating, the engineered As/AsxOy@PDA@M NSs serve as an intelligent theranostic platform with active tumor targeting and long-term blood circulation. Given its narrow-band-gap-enabled in vivo fluorescence imaging properties, As/AsxOy@PDA@M NSs could be applied as an imaging-guided non-invasive and real-time nanomedicine for cancer therapy.

Synergy between indigenous bacteria and extracellular electron shuttles enhances transformation and mobilization of Fe(III)/As(V)

The reduction of Fe(III) by metal-reducing bacteria through extracellular electron transfer (EET) is a critical link in the biogeochemical cycle of As/Fe, and humic substances are believed to play a role in this process. In this study, the indigenous As-resistant bacterium Bacillus D2201 isolated from the Datong Basin was responsible for the valence transition of Fe and As in the groundwater environment. The bacterium has both the arsC gene for intracellular arsenate reduction and an EET pathway for transferring electrons to an electrode or Fe(III). Chronoamperometry showed that 3.0- and 10.2-fold increases in the output current density were achieved by injecting 0.05 and 0.5 mM AQDS with an inoculation of Bacillus D2201. Interestingly, Fe(III) bio-reduction is not only regulated by AQDS, but also by As(V) stimulation. The increase in pyruvate consumption and levels of intracellular glutathione (GSH) suggest that As pressure promotes cell metabolism and the consumption of electron donors for Fe(III) reduction with strain D2201. The reduction and dissolution of Fe(III) mineral regulated by AQDS dominated the release and mobilization of As. Compared with the AQDS-free treatment, 5.5-, 6.6-, and 7.2-fold increases in the amounts of Fe(II) were released with the addition of 0.1, 0.5, and 1 mM AQDS, respectively, and approximately 2.6-, 2.8-, and 3.2-fold increases in the As(V) levels were observed under the same conditions. These insights have profound environmental implications with respect to the effect of AQDS and As stress on EET and Fe(III) reduction in arsenic-resistant bacteria.

A Systematic Strategy of Combinational Blow for Overcoming Cascade Drug Resistance via NIR-Light-Triggered Hyperthermia.

A systematic combination strategy is proposed for overcoming cisplatin resistance using near-infrared (NIR)-light-triggered hyperthermia. A new photothermal polymer DAP-F is complexed with a reduction-sensitive amphiphilic polymer P1 to form F-NPs with photothermal effect. Subsequently, to build the final nanosystem F-Pt-NPs, F-NPs are combined with Pt-NPs, which are obtained by encapsulating a Pt(IV) prodrug with P1. Mild hyperthermia (43 °C), generated from F-Pt-NPs induced by an 808 nm NIR laser, have various effects such as: i) enhancing the cellular membrane permeability to promote the uptake of drugs; ii) activating cisplatin by accelerating the glutathione consumption; iii) increasing the Pt-DNA adducts formation and possibly the formation of a portion of irreparable Pt-DNA interstrand crosslinks, thereby inhibiting the repair of DNA. In vitro, it is found that even on cisplatin-resistant A549DDP cells, the IC50 of F-Pt-NPs (43 °C) is only 7.0 × 10-6 m Pt mL-1 . In vivo, on a patient-derived xenograft model of multidrug resistant lung cancer, the efficacy of the F-Pt-NPs (43 °C) treatment group shows a tumor inhibition rate of 94%. Taken together, here, an important perspective of resolving cascade drug resistance with the assistance of mild hyperthermia triggered by NIR light is presented, which can be of great significance for clinic translation.

Cell-based high-throughput screening for the evaluation of reactive metabolite formation potential

Here, we established a high-throughput in vitro assay system to predict reactive metabolite (RM) formation. First, we performed the glutathione (GSH) consumption assay to monitor GSH levels as an index of RM formation potential using HepaRG cells pretreated with 500 μM D,L-buthionine-(S,R)-sulfoximine (BSO) and then treated with ticlopidine and diclofenac. Both drugs, under GSH-reduced conditions, significantly decreased relative cellular GSH content by 70% and 34%, respectively, compared with that in cells not pretreated with BSO. Next, we examined the correlation between GSH consumption and covalent binding assays; the results showed good correlation (correlation coefficient = 0.818). We then optimized the test compound concentration for evaluating RM formation potential using 76 validation compound sets, and the highest sensitivity (53%) was observed at 100 μM. Finally, using HepG2 cells, PXB-cells, and human primary hepatocytes, we examined the cell types suitable for evaluating RM formation potential. The expression of CYP3A4 was highest in HepaRG cells, suggesting the highest sensitivity (56.4%) of the GSH consumption assay. Moreover, a co-culture model of PXB-cells and HepaRG cells showed high sensitivity (72.7%) with sufficient specificity (85.7%). Thus, the GSH consumption assay can be used to effectively evaluate RM formation potential in the early stages of drug discovery.

CPI-1189 protects neuronal cells from oxygen glucose deprivation/re-oxygenation-induced oxidative injury and cell death.

Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) induces profound oxidative injury and neuronal cell death. It mimics ischemia-reperfusion neuronal injury. CPI-1189 is a novel tumor necrosis factor alpha-inhibiting compound with potential neuroprotective function. Here in SH-SY5Y neuronal cells and primary murine cortical neurons, CPI-1189 pretreatment potently inhibited OGDR-induced viability reduction and cell death. In OGDR-stimulated neuronal cells, p38 phosphorylation was blocked by CPI-1189. In addition, CPI-1189 alleviated OGDR-induced reactive oxygen species production, lipid peroxidation, and glutathione consumption. OGDR-induced neuronal cell apoptosis was also inhibited by CPI-1189 pretreatment. Furthermore, in SH-SY5Y cells and cortical neurons, CPI-1189 alleviated OGDR-induced programmed necrosis by inhibiting mitochondrial p53-cyclophilin D-adenine nucleotide translocase 1 association, mitochondrial depolarization, and lactate dehydrogenase release to the medium. In summary, CPI-1189 potently inhibited OGDR-induced oxidative injury and neuronal cell death.

Parallel Lipid Peroxide Accumulation Strategy Based on Bimetal-Organic Frameworks for Enhanced Ferrotherapy.

Ferroptosis, a nonapoptotic cell-death pathway, is commonly regulated by ether lipid peroxide generation or glutathione consumption. In this work, a parallel lipid peroxide accumulation strategy was designed based on catalytic metal-organic frameworks (MOFs) for enhanced ferrotherapy. The bimetallic MOF was synthesized with iron porphyrin as a linker and cupric ion as a metal node, and erastin, a ferroptosis inducer, was sandwiched between the MOF layers with 4,4'-dipyridyl disulfide as spacers. In a tumor microenvironment, erastin was released from the layered MOFs through glutathione-responsive cleavage. The exfoliated MOFs served as a dual Fenton reaction inducer to generate numerous hydroxyl radicals for the accumulation of lipid peroxide, while erastin-aggravated glutathione depletion down-regulated glutathione peroxidase 4; this then inhibited the consumption of lipid peroxide. Therefore, a parallel lipid peroxide accumulation strategy was established for enhanced ferrotherapy that effectively inhibited tumor growth in live mice, opening up new opportunities to treat apoptosis-insensitive tumors.

Commentary: Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness?

Commentary: Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness?

PSMA-targeted arsenic nanosheets: a platform for prostate cancer therapy via ferroptosis and ATM deficiency-triggered chemosensitization.

Ferroptosis, a newly recognized form of non-apoptotic cell death, has recently been introduced for effective cancer therapy. The reported ferroptosis-inducing nanomaterials mainly consisted of metal-based components. Herein, we designed an inorganic metal-free nanoplatform, PSMA-targeted arsenic nanosheets (PMANs), which simultaneously increased glutathione (GSH) consumption, suppressed solute carrier family 7 member 11 (SLC7A11) and glutathione-dependent peroxidase 4 (GPX4) expression, and promoted the generation of reactive oxygen species (ROS) and lipid peroxides (LPO). In addition, owing to the large surface area, PMANs efficiently transported doxorubicin (DOX) to prostate cancer for synergistic therapy. Surprisingly, we found that PMANs could sensitize prostate cancer cells to DOX through downregulating the expression of ataxia telangiectasia mutated (ATM), which further augmented the GPX4 downregulation-mediated ferroptotic tumoricidal effect. Given that arsenic trioxide has been routinely and successfully used in the clinical treatment of leukemia for a long time, we anticipate that PMANs will offer a promising strategy for prostate cancer therapy.

Tumor Microenvironment Responsive Biodegradable Fe-Doped MoOx Nanowires for Magnetic Resonance Imaging Guided Photothermal-Enhanced Chemodynamic Synergistic Antitumor Therapy.

Rational design of nanosystems that target tumor microenvironment have attracted widespread attention. However, it is still a great challenge to make a multifunctional nanoplatform that actively and selectively interacts with tumor microenvironment, without causing toxicity to surrounding normal tissues. Herein, the biodegradable Fe-doped MoOx (FMO) nanowires are designed as an anti-tumor nanoreagent that possesses great photothermal conversion ability (48.5%) and magnetic properties for T1 weighted magnetic resonance imaging (MRI). Also, FMO can be used as a chemodynamic therapy (CDT) reagent to effectively catalyze the decomposition of H2 O2 and produce hydroxyl radical (·OH). At the same time, the consumption of glutathione will also enhance the CDT effect. More importantly, FMO presents pH-dependent degradation behavior: rapid degradation at physiological pH, but relatively stable at acidic pH. In vivo anti-tumor experiment demonstrates that the FMO is able to effectively inhibit the tumor growth with minimal side effects. Generally speaking, these results indicate that the FMO has huge potential for MRI image-guided cancer therapy and promotes the clinical translation of nanodrugs.

Ferritin reduction is essential for cerebral ischemia-induced hippocampal neuronal death through p53/SLC7A11-mediated ferroptosis

Cerebral ischemia is the most common cause of hippocampal neuronal death and the most prevalent cause of stroke with high mortality rate. Ferroptosis has been suggested to affect the role of hippocampal neurons. This study explores the influence of lentivirus infection-induced ferritin overexpression in hippocampal neuronal injury and death through simulations in August Copenhagen Irish rat models. Twenty-four-hour cerebral ischemia–reperfusion injury was induced in the rats after 90-min middle cerebral artery occlusion (MCAO). Ferritin overexpression was induced through lentivirus infection. The Morris Water Maze (MWM) test and tau hyperphosphorylation test were performed on hippocampal neurons to establish a MCAO model. The effect of ferritin overexpression on hippocampal neuronal death was evaluated using hematoxylin–eosin staining and annexin V/propidium iodide flow cytometry. The MWM test revealed that MCAO modeling decreased the cognitive and locomotor capacity of the rats, whereas ferritin overexpression partially reversed the effect of MCAO. In addition, the hyperphosphorylation of tau caused by MCAO was reduced by ferritin. Pathogenic changes, impaired viability, increased apoptosis, and elevated caspase-9 cleavage in hippocampal neurons were clearly recovered by ferritin. Moreover, robust reactive oxygen species production and glutathione consumption, which was induced by MCAO modeling, were ameliorated by ferritin. Furthermore, two key modulators of ferroptosis, p53 and SLC7A11, were demonstrated to be upregulated by MCAO modeling and downregulated by ferritin. Ferritin reduction is essential for cerebral ischemia-induced hippocampal neuronal ferroptosis mediated via p53 and SLC7A11.

Nanomedicine enables autophagy-enhanced cancer-cell ferroptosis

Ferroptosis and autophagy, playing significant roles in tumor treatment, are two typical forms of the programmed cell death. However, the rational combination of ferroptosis and autophagy for synergistic tumor therapy is still highly challenging. Herein, we report on an intriguing nanomedicine strategy for achieving autophagy-enhanced ferroptosis on efficiently combating cancer, which was based on the construction of trehalose-loaded mSiO2@MnOx-mPEG (TreMMM) nanoparticles with satisfactory biocompatibility. The nanoparticles are endowed with high glutathione (GSH) consumption efficiency, thereby inducing cancer-cell ferroptosis via inactivating glutathione peroxidases 4 (GPX4). Subsequently, the TreMMM degradation due to the GSH depletion and pH sensitivity contributed to the trehalose release for inducing autophagy, promoting/enhancing ferroptosis by NCOA4-mediated degradation of ferritin. A substantial in vitro and in vivo antitumor effect was achieved by such an intriguing autophagy-enhanced ferroptosis. Therefore, the rational combination of GSH-consumption-induced ferroptosis and trehalose-induced autophagy by nanomedicine design provides an alternative but effective strategy for tumor treatment.

Light-activatable liposomes for repetitive on-demand drug release and immunopotentiation in hypoxic tumor therapy

External stimuli-responsive nanomedicine with desirable repetitive on-demand drug release character is postulated to greatly accommodate patients' flexible medication regime. To this object, light-activatable liposomes (Pt/Ce6-LP) integrated with both a Ce6 photodynamic component and a tetravalent platinum prodrug (Pt(IV)) chemotherapeutic component are engineered. This multifunctional system was rationally designed using unsaturated phospholipid to achieve repetitive on-demand drug release under discontinuous light irradiation, thus performing chemo-photodynamic therapy effect and immunopotentiation in hypoxic tumor. Furthermore, glutathione (GSH) consumption during transformation from Pt(IV) prodrug to Pt(II) can avoid depletion of reactive oxygen species (ROS) in photodynamic therapy (PDT). Note this positive feedback loop appears to remodel the redox balance of H2O2 and GSH in tumors, alleviating the hypoxic tumor microenvironment. The alleviated hypoxia is found to be critical to the enhancement of PDT efficacy, reversal of cisplatin resistance in tumors, and polarization of tumor-associated macrophages (TAMs) to the immunocompetent M1-phynotype. Pt/Ce6-LP with light radiation demonstrates significant antitumor effect and persistent post-medication inhibition in patient-derived tumor xenograft model of hepatocellular carcinoma.

Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness?

COVID-19 pandemic is posing an unprecedented sanitary threat: antiviral and host-directed medications to treat the disease are urgently needed. A great effort has been paid to find drugs and treatments for hospitalized, severely ill patients. However, medications used for the domiciliary management of early symptoms, notwithstanding their importance, have not been and are not presently regarded with the same attention and seriousness. In analogy with other airways viral infections, COVID-19 patients in the early phase require specific antivirals (still lacking) and non-etiotropic drugs to lower pain, fever, and control inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (PAC) are widely used as non-etiotropic agents in common airways viral infections and hence are both theoretically repurposable for COVID-19. However, a warning from some research reports and National Authorities raised NSAIDs safety concerns because of the supposed induction of angiotensin-converting enzyme 2 (ACE2) levels (the receptor used by SARS-CoV2 to enter host airways cells), the increased risk of bacterial superinfections and masking of disease symptoms. As a consequence, the use of NSAIDs was, and is still, discouraged while the alternative adoption of paracetamol is still preferred. On the basis of novel data and hypothesis on the possible role of scarce glutathione (GSH) levels in the exacerbation of COVID-19 and of the GSH depleting activity of PAC, this commentary raises the question of whether PAC may be the better choice.

Rapid Decomposition and Catalytic Cascade Nanoplatforms Based on Enzymes and Mn-Etched Dendritic Mesoporous Silicon for MRI-Guided Synergistic Therapy

The endogenous tumor microenvironment (TME) can signally influence the therapeutic effects of cancer, so it is necessary to explore effective synergistic therapeutic strategies based on changing of the TME. Here, a catalytic cascade nanoplatform based on manganese (Mn)-etched dendritic mesoporous silicon nanoparticles (designated as DMMnSiO3 NPs) loaded with indocyanine green (ICG) and natural glucose oxidase (GOD) is established (designated as DIG nanocomposites). As the Mn-O bonds in DMMnSiO3 NPs are susceptive to mildly acidic and reducing environments, the DIG nanocomposites can be rapidly decomposed because of the biodegradation of DMMnSiO3 NPs once internalized into the tumor by the consumption of glutathione (GSH) in TME to weaken the antioxidant capability of the tumors. The released Mn2+ could catalyze endogenous hydrogen peroxide (H2O2) to generate oxygen (O2) to relieve the hypoxia in TME. The generation of O2 may promote the catalyzed oxidation of glucose by GOD, which will cut off nutrient supplies, accompanied by the regeneration of H2O2. The regenerated H2O2 could be sequentially catalyzed by Mn2+ to compensate for the consumed O2, and thus, the catalytic cascade process between Mn2+ and GOD was set up. As a result, a synergistic therapeutic strategy based on T1-weighted magnetic resonance imaging (MRI) of Mn2+, starvation therapy by O2-compensation enhanced catalyzing glucose, dual-model (GSH consumption and O2 compensation) enhanced photodynamic therapy, and effective photothermal therapy of ICG (η = 23.8%) under 808 nm laser irradiation has been successfully established.

Ferroptosis in Neurological Diseases.

Ferroptosis is mechanism for non-apoptotic, iron-dependent, oxidative cell death that is characterized by glutathione consumption and lipid peroxides accumulation. Ferroptosis is crucially involved in neurological diseases, including neurodegeneration, stroke and neurotrauma. This review provides detailed discussions of the ferroptosis mechanisms in these neurological diseases. Moreover, it summarizes recent drugs that target ferroptosis for neurological disease treatment. Furthermore, it compares the differences and relationships among the various cell death mechanisms involved in neurological diseases. Elucidating the ferroptosis role in the brain can improve the understanding of neurological disease mechanism and provide potential prevention and treatment interventions for acute and chronic neurological diseases.

Toxicity Alleviation of Carbon Dots from Roast Beef after the Formation of Protein Coronas with Human Serum Albumin.

The unique properties of nanoparticles produced during food thermal processing have attracted considerable attention. In this study, the formation of protein coronas of fluorescent carbon dots (CDs) in roast beef with human serum albumin (HSA) and the corona effect on toxicity were reported. The CDs were roughly spherical with a size in the range of 1-5 nm, which were mainly composed of carbon (68.68%), nitrogen (10.6%), and oxygen (15.98%). The CDs could readily pass through the intestine wall due to their small size and good water solubility. There was an obvious interaction between HSA and CDs, suggesting that the CDs could form protein coronas. Thermodynamic analysis results of ΔH < 0 (-13.17 ± 3.74 kJ/mol) and ΔS > 0 ( 28.04 J/mol/K) indicated that the binding of HSA-CDs was due to electrostatic interactions or hydrophobic forces. The HSA-CD coronas were distributed in the lysosomes of the cells, alleviated swelling caused by the CDs, and inhibited the decrease of mitochondrial membrane potential caused by CDs. Furthermore, the protein coronas reduced cellular reactive oxygen species production and alleviated the consumption of glutathione by the CDs, thus protecting the cells from damage. This finding provided valuable information about protein coronas in ameliorating cytotoxicity.

Sulfated Polysaccharide from Digenea simplex Decreases Intestinal Inflammation in Rats

Sulfated polysaccharides derived from seaweeds have important biological activities. The aim of this work was to demonstrate the anti-inflammatory effect of a sulfated polysaccharide extracted from the seaweed Digenea simplex (Wulfen) C. Agardh 1822 on 2,4,6-trinitrobenzene sulfonic acid–induced colitis in rats. After inducing colitis, rats were euthanized, and the colon was excised to determine macroscopic lesion scores and wet weight and to histologically evaluate and quantify glutathione, malondialdehyde, myeloperoxidase, nitrate/nitrite, and cytokines. The polysaccharide, composed of β-d-galactose and 3,6-α-l-anhydrogalactose residues, reduced wet weight as well as macroscopic and microscopic lesion scores. It also reduced myeloperoxidase activity; reduced proinflammatory cytokines, malondialdehyde, and nitrate/nitrite levels; and preserved glutathione consumption in the colon. According to these results, we can infer that the sulfated polysaccharide derived from D. simplex has an anti-inflammatory effect on induced colitis in vivo.

Modulation of tumor microenvironment by metal-organic-framework-derived nanoenzyme for enhancing nucleus-targeted photodynamic therapy

Photodynamic therapy (PDT) is a promising strategy for tumor treatment. Still, its therapeutic efficacy is compromised by the unsatisfactory cytotoxicity to specific subcellular organelles and insidious tumor microenvironment properties like hypoxia and high glutathione levels. Here, we fabricated a novel nanoenzyme that derived from metal-organic framework (MOF) with intrinsic catalase-like activities to decompose H2O2 to O2 and simultaneous glutathione consumption for enhancing PDT efficacy. The obtained Mn3O4 nanoparticle shows a larger pore size and surface area compared to native MOF particles, which can be used to load high dose photosensitizer. When decorated with AS1411 aptamer and polyethylene glycol (PEG), the obtained Mn3O4-PEG@C&A particle exhibits excellent stability and cell nucleus targeting ability. Remarkably, Mn3O4-PEG@C&A particle inhibited the tumor growth in the mouse model with high efficacy without any biotoxicity. This is the first report that applied MOF-derived nanoparticle to nucleus-targeted PDT. It may provide a new approach for designing functional nanoenzyme to subcellular organelles-targeted tumor modulation.

Two-dimensional highly oxidized ilmenite nanosheets equipped with Z-scheme heterojunction for regulating tumor microenvironment and enhancing reactive oxygen species generation

Excessive reactive oxygen species (ROS), as effective cancer therapeutic agents, can promote tumor apoptosis. However, the clinical applications of ROS-mediated cancer therapies still have many limitations, such as self-defects of traditional photosensitizer, adverse tumor microenvironment (TME), and insufficient ROS production. Here, two-dimensional and highly oxidized ilmenite nanosheets (HOIL NSs, formula: FeTiO3@Fe2O3), one of perovskite analogues, were developed through combining ball-milling, probe sonication assisted liquid exfoliation, and probe sonication assisted surface oxidation. The HOIL NSs with surface oxidized Fe2O3 shell and FeTiO3 core cleverly developed a direct Z-scheme heterojunction, in which much stronger oxidation and reduction potentials in the valence band (VB) of Fe2O3 and the conduction band (CB) of FeTiO3 respectively were obtained via recombining the electrons in the CB of Fe2O3 with the holes in the VB of FeTiO3. Under irradiation of 650 nm laser, the generation of O2− from O2 and OH from OH− on the CB of FeTiO3 and VB of Fe2O3, respectively, were enhanced largely. Besides, the Fe2O3 shell and Fe3+/Fe2+ inside HOIL NSs can not only damage the TME through glutathione consumption and O2 production, but also produce OH by Fenton reaction. Moreover, the NSs can be triggered by an 808 nm laser to generate local hyperthermia for photothermal therapy. The fluorescent and photothermal imaging capabilities of the HOIL-PEG NSs also allow dual-modal imaging-guided cancer therapy.