Ferroptosis by nanomaterials: targeting cancer stem cells and overcoming drug resistance

Abstract

Tumor ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for combating cancers, particularly in cases involving cancer stem cells (CSCs) and drug resistance. In recent years nanomaterial-based approaches have gained significant attention for the potential to selectively induce ferroptosis in cancer cells while sparing normal tissues. This review aims to provide a comprehensive overview of the current state-of-the-art in utilizing nanomaterials for targeting tumor ferroptosis with a specific focus on the application in eradicating CSCs and overcoming drug resistance mechanisms. The molecular mechanisms underlying ferroptosis induction by nanomaterials, the unique properties and functionalities of various nanomaterial platforms, and strategies for targeting CSCs and overcoming drug resistance using nanoferroptosis approaches will be discussed. In addition, the preclinical and clinical evidence supporting the efficacy of nanomaterial platforms will be evaluated. Furthermore, the challenges and future perspectives in the development and translation of nanoferroptosis-based therapies for precision cancer treatment will be highlighted.

Keywords

Ferroptosis / drug resistance / cancer stem cell / nanomaterials

References

[1] Si W, Shen J, Zheng H, Fan W: The Role and Mechanisms of Action of MicroRNAs in Cancer Drug Resistance. Clinical Epigenetics 2019, 11: 1-24.

[2] Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H, et al.: Molecular Targeting Therapy of Cancer: Drug Resistance, Apoptosis and Survival Signal. Cancer Science 2003, 94: 15-21.

[3] O’Brien MA, Kirby R: Apoptosis: A Review of Pro-apoptotic and Anti-apoptotic Pathways and Dysregulation in Disease. Journal of Veterinary Emergency and Critical Care 2008, 18: 572-585.

[4] Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D’Orazi G: Apoptosis as Anticancer Mechanism: Function and Dysfunction of Its Modulators and Targeted Therapeutic Strategies. Aging (Albany NY) 2016, 8: 603-619.

[5] Singh R, Letai A, Sarosiek K: Regulation of Apoptosis in Health and Disease: The Balancing Act of BCL-2 Family Proteins. Nature Reviews Molecular Cell Biology 2019, 20: 175-193.

[6] Adams JM, Cory S: The Bcl-2 Apoptotic Switch in Cancer Development and Therapy. Oncogene 2007, 26: 1324-1337.

[7] Batlle E, Clevers H: Cancer Stem Cells Revisited. Nature Medicine 2017, 23: 1124-1134.

[8] Yu Z, Pestell TG, Lisanti MP, Pestell RG: Cancer Stem Cells. The International Journal of Biochemistry & Cell Biology 2012, 44: 2144-2151.

[9] Li Y, Wang Z, Ajani JA, Song S: Drug Resistance and Cancer Stem Cells. Cell Communication and Signaling 2021, 19: 19.

[10] Verma P, Shukla N, Kumari S, Ansari MS, Gautam NK, Patel GK: Cancer Stem Cell in Prostate Cancer Progression, Metastasis and Therapy Resistance. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2023, 1878: 188887.

[11] Zhang C, Liu X, Jin S, Chen Y, Guo R: Ferroptosis in Cancer Therapy: A Novel Approach to Reversing Drug Resistance. Molecular Cancer 2022, 21: 47.

[12] Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al.: Ferroptosis: Past, Present and Future. Cell Death & Disease 2020, 11: 88.

[13] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al.: Ferroptosis: An Iron-dependent form of Nonapoptotic Cell Death. Cell 2012, 149: 1060-1072.

[14] Chen Z, Wang W, Abdul Razak SR, Han T, Ahmad NH, Li X: Ferroptosis as a Potential Target for Cancer Therapy. Cell Death & Disease 2023, 14: 460.

[15] Shibue T, Weinberg RA: EMT, CSCs, and Drug Resistance: The Mechanistic Link and Clinical Implications. Nature Reviews Clinical Oncology 2017, 14: 611-629.

[16] Elgendy SM, Alyammahi SK, Alhamad DW, Abdin SM, Omar HA: Ferroptosis: An Emerging Approach for Targeting Cancer Stem Cells and Drug Resistance. Critical Reviews in Oncology/Hematology 2020, 155: 103095.

[17] Longley DB, Johnston PG: Molecular Mechanisms of Drug Resistance. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland 2005, 205: 275-292.

[18] Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B: The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Advanced Pharmaceutical Bulletin 2017, 7: 339-348.

[19] White TC, Marr KA, Bowden RA: Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clinical Microbiology Reviews 1998, 11: 382-402.

[20] Szymczyk J, Sluzalska KD, Materla I, Opalinski L, Otlewski J, Zakrzewska M: FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance. Cancers (Basel) 2021, 13: 5796.

[21] Brooks AN, Kilgour E, Smith PD: Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer. Clinical Cancer Research 2012, 18: 1855-1862.

[22] Davidsen KT, Haaland GS, Lie MK, Lorens JB, Engelsen AS: The Role of Axl Receptor Tyrosine Kinase in Tumor Cell Plasticity and Therapy Resistance. Biomarkers of the Tumor Microenvironment: Basic Studies and Practical Applications 2017, 351-376.

[23] Alfarouk KO, Stock C-M, Taylor S, Walsh M, Muddathir AK, Verduzco D, et al.: Resistance to Cancer Chemotherapy: Failure in Drug Response from ADME to P-gp. Cancer Cell International 2015, 15: 71.

[24] Bansal T, Jaggi M, Khar RK, Talegaonkar S: Emerging Significance of Flavonoids as P-glycoprotein Inhibitors in Cancer Chemotherapy. Journal of Pharmacy & Pharmaceutical Sciences 2009, 12: 46-78.

[25] Tian Y, Lei Y, Wang Y, Lai J, Wang J, Xia F: Mechanism of Multidrug Resistance to Chemotherapy Mediated by P-glycoprotein (Review). International Journal of Oncology 2023, 63: 119.

[26] Zhu DL, Tuo XM, Rong Y, Zhang K, Guo Y: Fibroblast Growth Factor Receptor Signaling as Therapeutic Targets in Female Reproductive System Cancers. Journal of Cancer 2020, 11: 7264-7275.

[27] Fresno Vara JÁ, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M: PI3K/Akt Signalling Pathway and Cancer. Cancer Treatment Reviews 2004, 30: 193-204.

[28] Toulany M, Rodemann HP: Phosphatidylinositol 3-kinase/Akt Signaling as a Key Mediator of Tumor Cell Responsiveness to Radiation. Seminars in Cancer Biology 2015, 35: 180-190.

[29] Vivanco I, Sawyers CL: The Phosphatidylinositol 3-kinase AKT Pathway in Human Cancer. Nature Reviews Cancer 2002, 2: 489-501.

[30] McCubrey JA, Steelman LS, Kempf CR, Chappell WH, Abrams SL, Stivala F, et al.: Therapeutic Resistance Resulting from Mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Signaling Pathways. Journal of Cellular Physiology 2011, 226: 2762-2781.

[31] Cassinelli G, Zuco V, Gatti L, Lanzi C, Zaffaroni N, Colombo D, et al.: Targeting the Akt Kinase to Modulate Survival, Invasiveness and Drug Resistance of Cancer Cells. Current Medicinal Chemistry 2013, 20: 1923-1945.

[32] Dong C, Wu J, Chen Y, Nie J, Chen C: Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer. Frontiers in Pharmacology 2021, 12: 628690.

[33] Jiang L, Wang P, Sun YJ, Wu YJ: Ivermectin Reverses the Drug Resistance in Cancer Cells Through EGFR/ERK/Akt/NF-kappaB Pathway. Journal of Experimental & Clinical Cancer Research 2019, 38: 265.

[34] Tan SF, Dunton W, Liu X, Fox TE, Morad SAF, Desai D, et al.: Acid Ceramidase Promotes Drug Resistance in Acute Myeloid Leukemia Through NF-κB-dependent P-glycoprotein Upregulation. Journal of Lipid Research 2019, 60: 1078-1086.

[35] Pradubyat N: The Effect of 1′Acetoxychavicol Acetate on Cell Proliferation, Metastasis, and Angiogenesis in Human Endocrine-resistant Breast Cancer Cells . United Kingdom: The University of Liverpool; 2020.

[36] Han E, Kim D, Cho Y, Lee S, Kim J, Kim H: Development of Polymersomes Co-Delivering Doxorubicin and Melittin to Overcome Multidrug Resistance. Molecules 2023, 28: 1087.

[37] De Lamirande E, Gagnon C: The Extracellular Signal-regulated Kinase (ERK) Pathway is Involved in Human Sperm Function and Modulated by the Superoxide Anion. Molecular Human Reproduction 2002, 8: 124-135.

[38] Xie L, Jing R, Qi J, Lin Z, Ju S: Drug Resistance-related MicroRNAs in Hematological Malignancies: Translating Basic Evidence into Therapeutic Strategies. Blood Reviews 2015, 29: 33-44.

[39] Najafi M, Farhood B, Mortezaee K, Kharazinejad E, Majidpoor J, Ahadi R: Hypoxia in Solid Tumors: A Key Promoter of Cancer Stem Cell (CSC) Resistance. Journal of Cancer Research and Clinical Oncology 2020, 146: 19-31.

[40] Najafi M, Farhood B, Mortezaee K: Cancer Stem Cells (CSCs) in Cancer Progression and Therapy. Journal of Cellular Physiology 2019, 234: 8381-8395.

[41] O’Brien CA, Kreso A, Jamieson CH: Cancer Stem Cells and Self-renewal. Clinical Cancer Research 2010, 16: 3113-3120.

[42] Aramini B, Masciale V, Grisendi G, Bertolini F, Maur M, Guaitoli G, et al.: Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence. Cancers 2022, 14: 976.

[43] Huang T, Song X, Xu D, Tiek D, Goenka A, Wu B, et al.: Stem Cell Programs in Cancer Initiation, Progression, and Therapy Resistance. Theranostics 2020, 10: 8721-8743.

[44] Raghav PK, Mann Z: Cancer Stem Cells Targets and Combined Therapies to Prevent Cancer Recurrence. Life Sciences 2021, 277: 119465.

[45] Zhang S, Zhu N, Li HF, Gu J, Zhang CJ, Liao DF, et al.: The Lipid Rafts in Cancer Stem Cell: A Target to Eradicate Cancer. Stem Cell Research & Therapy 2022, 13: 432.

[46] Yang Y, Li X, Wang T, Guo Q, Xi T, Zheng L: Emerging Agents that Target Signaling Pathways in Cancer Stem Cells. Journal of Hematology & Oncology 2020, 13: 60.

[47] An SM, Ding Q, Zhang J, Xie J, Li L: Targeting Stem Cell Signaling Pathways for Drug Discovery: Advances in the Notch and Wnt Pathways. Science China Life Sciences 2014, 57: 575-580.

[48] Ebrahimi N, Afshinpour M, Fakhr SS, Kalkhoran PG, Shadman-Manesh V, Adelian S, et al.: Cancer Stem Cells in Colorectal Cancer: Signaling Pathways Involved in Stemness and Therapy Resistance. Critical Reviews in Oncology/Hematology 2023, 182: 103920.

[49] Matsui WH: Cancer Stem Cell Signaling Pathways. Medicine (Baltimore) 2016, 95: S8-S19.

[50] Fu Y, Chang H, Peng X, Bai Q, Yi L, Zhou Y, et al.: Resveratrol Inhibits Breast Cancer Stem-like Cells and Induces Autophagy via Suppressing Wnt/β-catenin Signaling Pathway. PLoS One 2014, 9: e102535.

[51] Kim JH, Park SY, Jun Y, Kim JY, Nam JS: Roles of Wnt Target Genes in the Journey of Cancer Stem Cells. International Journal of Molecular Sciences 2017, 18: 1604.

[52] De Angelis ML, Francescangeli F, Zeuner A: Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities. Cancers 2019, 11: 1569.

[53] Gandhirajan RK, Poll-Wolbeck SJ, Gehrke I, Kreuzer K-A: Wnt/β-catenin/LEF-1 Signaling in Chronic Lymphocytic Leukemia (CLL): A Target for Current and Potential Therapeutic Options. Current Cancer Drug Targets 2010, 10: 716-727.

[54] Kypta RM, Waxman J: Wnt/β-catenin Signalling in Prostate Cancer. Nature Reviews Urology 2012, 9: 418-428.

[55] Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova II: Therapy Resistance Mediated by Cancer Stem Cells. Seminars in Cancer Biology 2018, 53: 156-167.

[56] Xiang J, Jiang M, Du X: The Role of Hippo Pathway in Ferroptosis. Frontiers in Oncology 2022, 12: 1107505.

[57] Zeng R, Dong J: The Hippo Signaling Pathway in Drug Resistance in Cancer. Cancers (Basel) 2021, 13: 318.

[58] Tang D, Chen X, Kang R, Kroemer G: Ferroptosis: Molecular Mechanisms and Health Implications. Cell Research 2021, 31: 107-125.

[59] Chen K, Jiang X, Wu M, Cao X, Bao W, Zhu LQ: Ferroptosis, a Potential Therapeutic Target in Alzheimer’s Disease. Frontiers in Cell and Developmental Biology 2021, 9: 704298.

[60] Wang H, Cheng Y, Mao C, Liu S, Xiao D, Huang J, et al.: Emerging Mechanisms and Targeted Therapy of Ferroptosis in Cancer. Molecular Therapy 2021, 29: 2185-2208.

[61] Su LJ, Zhang JH, Gomez H, Murugan R, Hong X, Xu D, et al.: Reactive Oxygen Species-induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis. Oxidative Medicine and Cellular Longevity 2019, 2019: 5080843.

[62] Jiang X, Stockwell BR, Conrad M: Ferroptosis: Mechanisms, Biology and Role in Disease. Nature Reviews Molecular Cell Biology 2021, 22: 266-282.

[63] Zhu L, Meng D, Wang X, Chen X: Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment. ACS Applied Bio Materials 2022, 5: 2481-2506.

[64] Lu B, Chen XB, Ying MD, He QJ, Cao J, Yang B: The Role of Ferroptosis in Cancer Development and Treatment Response. Frontiers in Pharmacology 2017, 8: 992.

[65] Ye L, Wen X, Qin J, Zhang X, Wang Y, Wang Z, et al.: Metabolism-Regulated Ferroptosis in Cancer Progression and Therapy. Cell Death & Disease 2024, 15: 196.

[66] Niu B, Liao K, Zhou Y, Wen T, Quan G, Pan X, et al.: Application of Glutathione Depletion in Cancer Therapy: Enhanced ROS-based Therapy, Ferroptosis, and Chemotherapy. Biomaterials 2021, 277: 121110.

[67] Zhao Y, Huang Z, Peng H: Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies. Frontiers in Oncology 2021, 11: 743006.

[68] Hao M, Jiang Y, Zhang Y, Yang X, Han J: Ferroptosis Regulation by Methylation in Cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 2023, 1878: 188972.

[69] Lee JY, Kim WK, Bae KH, Lee SC, Lee E-W: Lipid Metabolism and Ferroptosis. Biology (Basel) 2021, 10: 184.

[70] Brindisi M, Fiorillo M, Frattaruolo L, Sotgia F, Lisanti MP, Cappello AR: Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway. Cells 2020, 9: 1819.

[71] Zhu J, Xiong Y, Zhang Y, Wen J, Cai N, Cheng K, et al.: The Molecular Mechanisms of Regulating Oxidative Stress-induced Ferroptosis and Therapeutic Strategy in Tumors. Oxidative Medicine and Cellular Longevity 2020, 2020: 8810785.

[72] Weaver K, Skouta R: The Selenoprotein Glutathione Peroxidase 4: from Molecular Mechanisms to Novel Therapeutic Opportunities. Biomedicines 2022, 10: 891.

[73] Cheng Y, Song Y, Chen H, Li Q, Gao Y, Lu G, et al.: Ferroptosis Mediated by Lipid Reactive Oxygen Species: A Possible Causal Link of Neuroinflammation to Neurological Disorders. Oxidative Medicine and Cellular Longevity 2021, 2021: 5005136.

[74] Xu H, Zhou S, Tang Q, Xia H, Bi F: Cholesterol Metabolism: New Functions and Therapeutic Approaches in Cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 2020, 1874: 188394.

[75] Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al.: Global Survey of Cell Death Mechanisms Reveals Metabolic Regulation of Ferroptosis. Nature Chemical Biology 2016, 12: 497-503.

[76] Jia YJ, Zhang Y, Ma XB, Wang Y, Tian YQ, He PX, et al.: Ferroptosis: Opportunities and Challenges in Cancer. Journal of Exploratory Research in Pharmacology 2023, 8: 242-252.

[77] Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al.: DHODH-mediated Ferroptosis Defence is a Targetable Vulnerability in Cancer. Nature 2021, 593: 586-590.

[78] Xue P, Zhuang H, Shao S, Bai T, Zeng X, Yan S: Engineering Biodegradable Hollow Silica/Iron Composite Nanozymes for Breast Tumor Treatment through Activation of the “Ferroptosis Storm”. ACS Nano 2024, 18: 25795-25812.

[79] Wang G, Wang JJ, Zhi-Min Z, Xu XN, Shi F, Fu XL: Targeting Critical Pathways in Ferroptosis and Enhancing Antitumor Therapy of Platinum Drugs for Colorectal Cancer. Science Progress 2023, 106: 00368504221147173.

[80] Li Z, Yang J, Ren B, Fan Q, Huang L, Guo S, et al.: Double-Layered Hollow Mesoporous Cuprous Oxide Nanoparticles for Double Drug Sequential Therapy of Tumors. Advanced Materials 2024, 36: e2313212.

[81] Peng H, Zhang X, Yang P, Zhao J, Zhang W, Feng N, et al.: Defect Self-assembly of Metal-organic Framework Triggers Ferroptosis to Overcome Resistance. Bioactive Materials 2023, 19: 1-11.

[82] Wu K, Zhang W, Chen H, Wu J, Wang X, Yang X, et al.: An Iron Oxyhydroxide-based Nanosystem Sensitizes Ferroptosis by a “Three-Pronged” Strategy in Breast Cancer Stem Cells. Acta Biomaterialia 2023, 160: 281-296.

[83] Zhang P, Fu J, Hu J, You Q, Yao X, Hua D, et al.: Evoking and Enhancing Ferroptosis of Cancer Stem Cells by a Liver-targeted and Metal-organic Framework-based Drug Delivery System Inhibits the Growth and Lung Metastasis of Hepatocellular Carcinoma. Chemical Engineering Journal 2023, 454: 140044.

[84] Ni Z, Nie X, Zhang H, Wang L, Geng Z, Du X, et al.: Atranorin Driven by Nano Materials SPION Lead to Ferroptosis of Gastric Cancer Stem Cells by Weakening the mRNA 5-hydroxymethylcytidine Modification of the Xc-/GPX4 Axis and Its Expression. International Journal of Medical Sciences 2022, 19: 1680-1694.

[85] Feng Q, Fang W, Guo Y, Hu P, Shi J: Nebulized Therapy of Early Orthotopic Lung Cancer by Iron-Based Nanoparticles: Macrophage-Regulated Ferroptosis of Cancer Stem Cells. Journal of American Chemical Society 2023, 145: 24153-24165.

[86] Wang J, Yang W, He X, Zhang Z, Zheng X: Assembling p53 Activating Peptide With CeO₂ Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor . Frontiers in Bioengineering and Biotechnology 2022, 10: 929536.

[87] Zhou M, Yang Z, Yin T, Zhao Y, Wang CY, Zhu GY, et al.: Functionalized Fe-Doped Carbon Dots Exhibiting Dual Glutathione Consumption to Amplify Ferroptosis for Enhanced Cancer Therapy. ACS Applied Materials & Interfaces 2023, 15: 53228-53241.

[88] Wang L, Fu H, Song L, Wu Z, Yu J, Guo Q, et al.: Overcoming AZD9291 Resistance and Metastasis of NSCLC via Ferroptosis and Multitarget Interference by Nanocatalytic Sensitizer Plus AHP-DRI-12. Small 2023, 19: e2204133.

[89] Abu-Serie MM, Abdelfattah EZA: Anti-metastatic Breast Cancer Potential of Novel Nanocomplexes of Diethyldithiocarbamate and Green Chemically Synthesized Iron Oxide Nanoparticles. International Journal of Pharmaceutics 2022, 627: 122208.

[90] Jin W, Sun Y, Wang J, Wang Y, Chen D, Fang M, et al.: Arsenic Trioxide Suppresses Lung Adenocarcinoma Stem Cell Stemness by Inhibiting m6A Modification to Promote Ferroptosis. American Journal of Cancer Research 2024, 14: 507-525.

[91] Abu-Serie MM: Targeted Ferroptotic Potency of Ferrous Oxide Nanoparticles-Diethyldithiocarbamate Nanocomplex on the Metastatic Liver Cancer. Frontiers in Pharmacology 2022, 13: 1089667.

[92] Zhang X, Yang S, Wang Q, Ye W, Liu S, Wang X, et al.: Tailored Theranostic Nanoparticles Cause Efficient Ferroptosis in Head and Neck Squamous Cell Carcinoma Through a Reactive Oxygen Species “Butterfly Effect”. Chemical Engineering Journal 2021, 423: 130083.

[93] Hou DY, Cheng DB, Zhang NY, Wang ZJ, Hu XJ, Li X, et al.: In vivo Assembly Enhanced Binding Effect Augments Tumor Specific Ferroptosis Therapy . Nature Communications 2024, 15: 454.

[94] Tsakiris N, Fauvet F, Ruby S, Puisieux A, Paquot A, Muccioli GG, et al.: Combined Nanomedicines Targeting Colorectal Cancer Stem Cells and Cancer Cells. Journal of Controlled Release 2020, 326: 387-395.

[95] Li H, Deng X, Zhang Z, Yang Z, Huang H, Ye X, et al.: Nitric Oxide/Paclitaxel Micelles Enhance Anti-liver Cancer Effects and Paclitaxel Sensitivity by Inducing Ferroptosis, Endoplasmic Reticulum Stress and Pyroptosis. RSC Advances 2023, 13: 31772-31784.

[96] Huang A, Li Q, Shi X, Gao J, Ma Y, Ding J, et al.: An Iron-containing Nanomedicine for Inducing Deep Tumor Penetration and Synergistic Ferroptosis in Enhanced Pancreatic Cancer Therapy. Materials Today Bio 2024, 27: 101132.

[97] He P, Xu S, Miao Z, Que Y, Chen Y, Li S, et al.: Anti-Her2 Affibody-decorated Arsenene Nanosheets Induce Ferroptosis Through Depleting Intracellular GSH to Overcome Cisplatin Resistance. Journal of Nanobiotechnology 2023, 21: 203.

[98] Wu C, Zhang F, Li B, Li Z, Xie X, Huang Y, et al.: A Self-Assembly Nano-Prodrug for Combination Therapy in Triple-Negative Breast Cancer Stem Cells. Small 2023, 19: e2301600.

[99] Zhang J, Zhou K, Lin J, Yao X, Ju D, Zeng X, et al.: Ferroptosis-enhanced Chemotherapy for Triple-negative Breast Cancer with Magnetic Composite Nanoparticles. Biomaterials 2023, 303: 122395.

[100] Yang C, Chen Z, Wei M, Hu S, Cai M, Wang N, et al.: A Self-amplified Ferroptosis Nanoagent that Inhibits the Tumor Upstream Glutathione Synthesis to Reverse Cancer Chemoresistance. Journal of Controlled Release 2023, 357: 20-30.

[101] Wu F, Du Y, Yang J, Shao B, Mi Z, Yao Y, et al.: Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity and Promote Programmed Cell Death. ACS Nano 2022, 16: 3647-3663.

[102] Sun J, Liu Q, Jiang Y, Cai Z, Liu H, Zuo H: Engineered Small Extracellular Vesicles Loaded with miR-654-5p Promote Ferroptosis by Targeting HSPB1 to Alleviate Sorafenib Resistance in Hepatocellular Carcinoma. Cell Death Discovery 2023, 9: 362.

[103] Chittineedi P, Mohammed A, Abdul Razab MKA, Mat Nawi N, Pandrangi SL: Polyherbal Formulation Conjugated to Gold Nanoparticles Induced Ferroptosis in Drug-resistant Breast Cancer Stem Cells through Ferritin Degradation. Frontiers in Pharmacology 2023, 14: 1134758.

[104] Abu-Serie MM, Osuka S, Heikal LA, Teleb M, Barakat A, Dudeja V: Diethyldithiocarbamate-Ferrous Oxide Nanoparticles Inhibit Human and Mouse Glioblastoma Stemness: Aldehyde Dehydrogenase 1A1 Suppression and Ferroptosis Induction. Frontiers in Pharmacology 2024, 15: 1363511.

[105] He C, Jiang Y, Guo Y, Wu Z: Amplified Ferroptosis and Apoptosis Facilitated by Differentiation Therapy Efficiently Suppress the Progression of Osteosarcoma. Small 2023, 19: 2302575.

[106] Li Y, Jiang C, Zhang X, Liao Z, Chen L, Li S, et al.: Inhibition of ABCC9 by Zinc Oxide Nanoparticles Induces Ferroptosis and Inhibits Progression, Attenuates Doxorubicin Resistance in Breast Cancer. Cancer Nanotechnology 2022, 13: 3.

[107] Wu C, Xu L, Shi L, Gao X, Li J, Zhu X, et al.: Supramolecularly Self-assembled Nano-twin Drug for Reversing Multidrug Resistance. Biomaterials Science 2018, 6: 2261-2269.

[108] Chen H, Yan Z, Wu S, Li F: A Glutathione-responsive Polyphenol-Constructed Nanodevice for Double Roles in Apoptosis and Ferroptosis. Colloids and Surfaces B: Biointerfaces 2021, 205: 111902.

[109] Zhu J, Wang X, Su Y, Shao J, Song X, Wang W, et al.: Multifunctional Nanolocks with GSH as the Key for Synergistic Ferroptosis and Anti-chemotherapeutic Resistance. Biomaterials 2022, 288: 121704.

[110] Chen X, Ma R, Fu Z, Su Q, Luo X, Han Y, et al.: Metal-phenolic Networks-encapsulated Cascade Amplification Delivery Nanoparticles Overcoming Cancer Drug Resistance via Combined Starvation/Chemodynamic/Chemotherapy. Chemical Engineering Journal 2022, 442: 136221.

[111] Han Y, Dong Z, Wang C, Li Q, Hao Y, Yang Z, et al.: Ferrous Ions Doped Calcium Carbonate Nanoparticles Potentiate Chemotherapy by Inducing Ferroptosis. Journal of Controlled Release 2022, 348: 346-356.

[112] Luo Y, Yu X, Yao Y, Zhu L, Qin W, Shan Z, et al.: Fe-Based Metal-Organic Frameworks with Ferroptosis Generation Ability for Remodeling Chemotherapy of Non-small Cell Lung Cancer. ACS Applied Nano Materials 2023, 6: 12744-12753.

[113] Zhi S, Zhang X, Zhang J, Wang XY, Bi S: Functional Nucleic Acids-Engineered Bio-Barcode Nanoplatforms for Targeted Synergistic Therapy of Multidrug-Resistant Cancer. ACS Nano 2023, 17: 13533-13544.

[114] Zhao Y, Zhao W, Lim YC, Liu T: Salinomycin-Loaded Gold Nanoparticles for Treating Cancer Stem Cells by Ferroptosis-Induced Cell Death. Molecular Pharmaceutics 2019, 16: 2532-2539.

[115] Zhu G, Chi H, Liu M, Yin Y, Diao H, Liu Z, et al.: Multifunctional “Ball-rod” Janus Nanoparticles Boosting Fenton Reaction for Ferroptosis Therapy of Non-small Cell Lung Cancer. Journal of Colloid and Interface Science 2022, 621: 12-23.

[116] Chen Y, Yao Z, Liu P, Hu Q, Huang Y, Ping L, et al.: A Self-assembly Nano-prodrug for Triple-negative Breast Cancer Combined Treatment by Ferroptosis Therapy and Chemotherapy. Acta Biomaterialia 2023, 159: 275-288.

[117] Yao Z, Hu Q, Jin P, Li B, Huang Y, Zhang F, et al.: A Self-Assembly Combined Nano-Prodrug to Overcome Gemcitabine Chemo-Resistance of Pancreatic Tumors. Advanced Functional Materials 2023, 33: 2214598.

[118] Zheng Y, Li X, Dong C, Ding L, Huang H, Zhang T, et al.: Ultrasound-Augmented Nanocatalytic Ferroptosis Reverses Chemotherapeutic Resistance and Induces Synergistic Tumor Nanotherapy. Advanced Functional Materials 2021, 32: 2107529.

[119] Sun N, Lei Q, Wu M, Gao S, Yang Z, Lv X, et al.: Metal-organic Framework-mediated siRNA Delivery and Sonodynamic Therapy for Precisely Triggering Ferroptosis and Augmenting ICD in Osteosarcoma. Materials Today Bio 2024, 26: 101053.

[120] Zhao Z, Wu Y, Liang X, Liu J, Luo Y, Zhang Y, et al.: Sonodynamic Therapy of NRP2 Monoclonal Antibody-Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy-Dependent Ferroptosis. Advanced Science 2023, 10: e2303872.

[121] Ge H, Du J, Zheng J, Xu N, Yao Q, Long S, et al.: Effective Treatment of Cisplatin-resistant Ovarian Tumors with a MoS₂-based Sonosensitizer and Nanoenzyme Capable of Reversing the Resistant-microenvironment and Enhancing Ferroptosis and Apoptosis . Chemical Engineering Journal 2022, 446: 137040.

[122] Zhou L, Dong C, Ding L, Feng W, Yu L, Cui X, et al.: Targeting Ferroptosis Synergistically Sensitizes Apoptotic Sonodynamic Anti-tumor Nanotherapy. Nano Today 2021, 39: 101212.

[123] Lin H, Xu Q, Zhang F, Wu H, Hu B, Chen G, et al.: Self-assembled Carrier-free Nanomedicine Suppresses Tumor Stemness to Overcome the Acquired Drug-resistance of Hepatocellular Carcinoma. Chemical Engineering Journal 2023, 474: 145555.

[124] Zhang C, Liu H, Gong M, Yang M, Yang Z, Xie Y, et al.: Biomimetic Gold Nanocages for Overcoming Chemoresistance of Osteosarcoma by Ferroptosis and Immunogenic Cell Death. Materials & Design 2021, 210: 110087.

[125] Deng K, Tian H, Zhang T, Gao Y, Nice EC, Huang C, et al.: Chemo-photothermal Nanoplatform with Diselenide as the Key for Ferroptosis in Colorectal Cancer. Journal of Controlled Release 2024, 366: 684-693.

[126] Cai Z, Huan ML, Zhang YW, Zhao TT, Han TY, He W, et al.: Tumor Targeted Combination Therapeutic System for the Effective Treatment of Drug Resistant Triple Negative Breast Cancer. International Journal of Pharmaceutics 2023, 636: 122821.

[127] Chen K, Zhou A, Zhou X, He J, Xu Y, Ning X: Cellular Trojan Horse Initiates Bimetallic Fe-Cu MOF-mediated Synergistic Cuproptosis and Ferroptosis Against Malignancies. Science Advances 2024, 10: eadk3201.

[128] Liu B, Ji Q, Cheng Y, Liu M, Zhang B, Mei Q, et al.: Biomimetic GBM-targeted Drug Delivery System Boosting Ferroptosis for Immunotherapy of Orthotopic Drug-resistant GBM. Journal of Nanobiotechnology 2022, 20: 161.

[129] Zhang N, Wang Z, Li G, Zhang M, Liu Q, Cai C, et al.: A Carrier-free Metal-phenolic Network with Enhanced Ferroptosis-immunotherapy for Overcoming Tumor Resistance and Metastasis. Chemical Engineering Journal 2024, 488: 150780.

[130] Song H, Sun H, He N, Xu C, Du L, Ji K, et al.: Glutathione Depletion-Induced Versatile Nanomedicine for Potentiating the Ferroptosis to Overcome Solid Tumor Radioresistance and Enhance Immunotherapy. Advanced Healthcare Materials 2024, 13: e2303412.

[131] Cao W, Zhang X, Feng Y, Li R, Lu A, Li Z, et al.: Lipid Nanoparticular Codelivery System for Enhanced Antitumor Effects by Ferroptosis-Apoptosis Synergistic with Programmed Cell Death-Ligand 1 Downregulation. ACS Nano 2024, 18: 17267-17281.

[132] Meng M, Zhang X, Li Q, Han J, Chen Y, Qiao H, et al.: Engineering M1-derived Nanovesicles Loading with Docosahexaenoic Acid Synergizes Ferroptosis and Immune Activation for Treating Hepatocellular Carcinoma. Cancer Nanotechnology 2023, 14: 17.

[133] Guo Y, Zhang X, Sun W, Jia H-R, Zhu Y-X, Zhang X, et al.: Metal-Phenolic Network-Based Nanocomplexes that Evoke Ferroptosis by Apoptosis: Promoted Nuclear Drug Influx and Reversed Drug Resistance of Cancer. Chemistry of Materials 2019, 31: 10071-10084.

[134] Le XT, Nguyen NT, Lee WT, Yang Y, Choi HG, Youn YS: Peroxidase-Mimicking Iron-Based Single-Atom Upconversion Photocatalyst for Enhancing Chemodynamic Therapy. Advanced Functional Materials 2024, 34: 2401893.

[135] Ma L, Huang H, Feng W, Chen L, Xia L, Yu Y, et al.: 2D Catalytic, Chemodynamic, and Ferroptotic Vermiculite Nanomedicine. Advanced Functional Materials 2022, 32: 2208220.

[136] Sang M, Luo R, Bai Y, Dou J, Zhang Z, Liu F, et al.: Mitochondrial Membrane Anchored Photosensitive Nano-device for Lipid Hydroperoxides Burst and Inducing Ferroptosis to Surmount Therapy-Resistant Cancer. Theranostics 2019, 9: 6209-6223.

[137] Zheng J, Du J, Ge H, Xu N, Yao Q, Long S, et al.: Viscosity-dependent Photocatalysis Triggers Ferroptosis and Type-I Photodynamic Therapy to Kill Drug-resistant Tumors. Chemical Engineering Journal 2022, 449: 136565.

[138] Liang J, Li L, Tian H, Wang Z, Liu G, Duan X, et al.: Drug Repurposing-Based Brain-Targeting Self-Assembly Nanoplatform Using Enhanced Ferroptosis against Glioblastoma. Small 2023, 19: e2303073.

[139] Zhu T, Shi L, Yu C, Dong Y, Qiu F, Shen L, et al.: Ferroptosis Promotes Photodynamic Therapy: Supramolecular Photosensitizer-Inducer Nanodrug for Enhanced Cancer Treatment. Theranostics 2019, 9: 3293-3307.

[140] Chi H, Zhu G, Yin Y, Diao H, Liu Z, Sun S, et al.: Dual-Responsive Multifunctional “Core-Shell” Magnetic Nanoparticles Promoting Fenton Reaction for Tumor Ferroptosis Therapy. International Journal of Pharmaceutics 2022, 622: 121898.

[141] Chen J, Wang Y, Han L, Wang R, Gong C, Yang G, et al.: A Ferroptosis-inducing Biomimetic Nanocomposite for the Treatment of Drug-resistant Prostate Cancer. Materials Today Bio 2022, 17: 100484.

[142] Yu H, Zhao H, Zhang Y, Hou Y, Li R, Liang T, et al.: A Biomimetic Nanoreactor for Combinational Chemo/Chemodynamic Therapy of Choriocarcinoma Through Synergistic Apoptosis and Ferroptosis Strategy. Chemical Engineering Journal 2023, 472: 144690.

[143] Guan Y, Lei H, Xing C, Yan B, Lin B, Yang X, et al.: Multimodal Nanoplatform with ROS Amplification to Overcome Multidrug Resistance in Prostate Cancer via Targeting P-Glycoprotein and Ferroptosis. Advanced Healthcare Materials 2024, 13: e2301345.

[144] Fu J, Li T, Yang Y, Jiang L, Wang W, Fu L, et al.: Activatable Nanomedicine for Overcoming Hypoxia-induced Resistance to Chemotherapy and Inhibiting Tumor Growth by Inducing Collaborative Apoptosis and Ferroptosis in Solid Tumors. Biomaterials 2021, 268: 120537.

[145] Jiang H, Tian H, Wang Z, Li B, Chen R, Luo K, et al.: Laser-activatable Oxygen Self-supplying Nanoplatform for Efficiently Overcoming Colorectal Cancer Resistance by Enhanced Ferroptosis and Alleviated Hypoxic Microenvironment. Biomaterials Research 2023, 27: 92.

[146] Du B, Zheng M, Ma H, Huang J, Jiao Q, Bai Y, et al.: Nanozyme-natural Enzymes Cascade Catalyze Cholesterol Consumption and Reverse Cancer Multidrug Resistance. Journal of Nanobiotechnology 2022, 20: 209.

[147] Cai X, Ruan L, Wang D, Zhang J, Tang J, Guo C, et al.: Boosting Chemotherapy of Bladder Cancer Cells by Ferroptosis Using Intelligent Magnetic Targeting Nanoparticles. Colloids and Surfaces B: Biointerfaces 2024, 234: 113664.

[148] Wang X, Zhao L, Wang C, Wang L, Wu H, Song X, et al.: Potent Nanoreactor-mediated Ferroptosis-based Strategy for the Reversal of Cancer Chemoresistance to Sorafenib. Acta Biomaterialia 2023, 159: 237-246.

[149] Chen Y, Li X, Luo K, Wang T, Liu T, Lu E, et al.: Hyperthermia/Glutathione-triggered Ferritin Nanoparticles Amplify the Ferroptosis for Synergistic Tumor Therapy. Materials Today Bio 2024, 26: 101085.

[150] Zhou H, Liu Z, Zhang Z, Pandey NK, Amador E, Nguyen W, et al.: Copper-cysteamine Nanoparticle-mediated Microwave Dynamic Therapy Improves Cancer Treatment with Induction of Ferroptosis. Bioactive Materials 2023, 24: 322-330.

[151] Huang Y, Lin J, Xiong Y, Chen J, Du X, Liu Q, et al.: Superparamagnetic Iron Oxide Nanoparticles Induce Ferroptosis of Human Ovarian Cancer Stem Cells by Weakening Cellular Autophagy. Journal of Biomedical Nanotechnology 2020, 16: 1612-1622.

[152] Gao M, Deng J, Liu F, Fan A, Wang Y, Wu H, et al.: Triggered Ferroptotic Polymer Micelles for Reversing Multidrug Resistance to Chemotherapy. Biomaterials 2019, 223: 119486.

[153] Zhao X, Wang X, Zhang W, Tian T, Zhang J, Wang J, et al.: A Ferroptosis-Inducing Arsenene-Iridium Nanoplatform for Synergistic Immunotherapy in Pancreatic Cancer. Angewandte Chemie International Edition in English 2024, 63: e202400829.

[154] Jiang J, Wang W, Zheng H, Chen X, Liu X, Xie Q, et al.: Nano-enabled Photosynthesis in Tumours to Activate Lipid Peroxidation for Overcoming Cancer Resistances. Biomaterials 2022, 285: 121561.

[155] Xiong H, Wang C, Wang Z, Jiang Z, Zhou J, Yao J: Intracellular Cascade Activated Nanosystem for Improving ER+ Breast Cancer Therapy Through Attacking GSH-mediated Metabolic Vulnerability. Journal of Controlled Release 2019, 309: 145-157.

[156] Yao X, Yang P, Jin Z, Jiang Q, Guo R, Xie R, et al.: Multifunctional Nanoplatform for Photoacoustic Imaging-guided Combined Therapy Enhanced by CO Induced Ferroptosis. Biomaterials 2019, 197: 268-283.

[157] Sun R, Ma W, Ling M, Tang C, Zhong M, Dai J, et al.: pH-activated Nanoplatform for Visualized Photodynamic and Ferroptosis Synergistic Therapy of Tumors. Journal of Controlled Release 2022, 350: 525-537.

[158] Mansur AAP, Mansur HS, Leonel AG, Carvalho IC, Lage MCG, Carvalho SM, et al.: Supramolecular Magnetonanohybrids for Multimodal Targeted Therapy of Triple-negative Breast Cancer Cells. Journal of Materials Chemistry B 2020, 8: 7166-7188.

[159] Tang L, Cao Y, Yin Y, Liu H, Feng J, Fu C, et al.: Dual-targeting Nanozyme Combined with aPD-L1-based Immunotherapy for Combating Cancer Recurrence and Metastasis. Materials Today 2024, 73: 79-95.

[160] Liu K, Huang L, Qi S, Liu S, Xie W, Du L, et al.: Ferroptosis: The Entanglement between Traditional Drugs and Nanodrugs in Tumor Therapy. Advanced Healthcare Materials 2023, 12: 2203085.

[161] Han S, Zou J, Xiao F, Xian J, Liu Z, Li M, et al.: Nanobiotechnology Boosts Ferroptosis: Opportunities and Challenges. Journal of Nanobiotechnology 2024, 22: 606.

[162] Dai E, Chen X, Linkermann A, Jiang X, Kang R, Kagan VE, et al.: A Guideline on the Molecular Ecosystem Regulating Ferroptosis. Nature Cell Biology 2024, 26: 1447-1457.

[163] Zhou H-M, Zhang J-G, Zhang X, Li Q: Targeting Cancer Stem Cells for Reversing Therapy Resistance: Mechanism, Signaling, and Prospective Agents. Signal Transduction and Targeted Therapy 2021, 6: 62.

[164] Overchuk M, Zheng G: Overcoming Obstacles in the Tumor Microenvironment: Recent Advancements in Nanoparticle Delivery for Cancer Theranostics. Biomaterials 2018, 156: 217-237.

[165] Jain A, Tiwari A, Verma A, Jain SK: Ultrasound-based Triggered Drug Delivery to Tumors. Drug Delivery and Translational Research 2018, 8: 150-164.

[166] Wang X, Wang X, Yue Q, Xu H, Zhong X, Sun L, et al.: Liquid Exfoliation of TiN Nanodots as Novel Sonosensitizers for Photothermal-enhanced Sonodynamic Therapy Against Cancer. Nano Today 2021, 39: 101170.

[167] Hu Q, Zuo H, Hsu JC, Zeng C, Tian Z, Sun Z, et al.: The Emerging Landscape for Combating Resistance Associated with Energy-Based Therapies via Nanomedicine. Advanced Materials 2024, 36: 2308286.

[168] Wu F, Zhang Q, Sun B, Chu X, Zhang M, She Z, et al.: MoO₃-x Nanosheets-based Platform for Single NIR Laser Induced Efficient PDT/PTT of Cancer . Journal of Controlled Release 2021, 338: 46-55.

[169] Lv Z, He S, Wang Y, Zhu X: Noble Metal Nanomaterials for NIR-Triggered Photothermal Therapy in Cancer. Advanced Healthcare Materials 2021, 10: 2001806.

[170] Overchuk M, Weersink RA, Wilson BC, Zheng G: Photodynamic and Photothermal Therapies: Synergy Opportunities for Nanomedicine. ACS Nano 2023, 17: 7979-8003.

[171] Zhuang H, Wang L, Shao S, Jing H, Xue P, Bai T, et al.: Photocatalysis-promoted Tumor Ferroptosis Enabled by MOF-derived Black TiO₂ . Chemical Engineering Journal 2024, 496: 154204.

[172] Tang J, Liu Y, Xue Y, Jiang Z, Chen B, Liu J: Endoperoxide-enhanced Self-assembled ROS Producer as Intracellular Prodrugs for Tumor Chemotherapy and Chemodynamic Therapy. Exploration 2024, 4: 20230127.

[173] Lin L, Wang S, Deng H, Yang W, Rao L, Tian R, et al.: Endogenous Labile Iron Pool-Mediated Free Radical Generation for Cancer Chemodynamic Therapy. Journal of the American Chemical Society 2020, 142: 15320-15330.

[174] Wang X, Zhong X, Liu Z, Cheng L: Recent Progress of Chemodynamic Therapy-induced Combination Cancer Therapy. Nano Today 2020, 35: 100946.

[175] Zhang Y, Zhang N, Xing J, Sun Y, Jin X, Shen C, et al.: In Situ Hydrogel Based on Cu-Fe₃O₄ Nanoclusters Exploits Oxidative Stress and the Ferroptosis/Cuproptosis Pathway for Chemodynamic Therapy . Biomaterials 2024, 311: 122675.

[176] He Y, Cong C, He Y, Hao Z, Li C, Wang S, et al.: Tumor Hypoxia Relief Overcomes Multidrug Resistance and Immune Inhibition for Self-enhanced Photodynamic Therapy. Chemical Engineering Journal 2019, 375: 122079.

[177] Yang J, He Y, Zhang M, Liang C, Li T, Ji T, et al.: Programmed Initiation and Enhancement of cGAS/STING Pathway for Tumour Immunotherapy via Tailor-designed ZnFe₂O₄-based Nanosystem . Exploration 2023, 3: 20230061.

[178] Yan S, Luo Z, Li Z, Wang Y, Tao J, Gong C, et al.: Improving Cancer Immunotherapy Outcomes Using Biomaterials. Angewandte Chemie International Edition 2020, 59: 17332-17343.

[179] Bai T, Xue P, Shao S, Yan S, Zeng X: Cholesterol Depletion-Enhanced Ferroptosis and Immunotherapy via Engineered Nanozyme. Advanced Science 2024, 11: 2405826.

[180] Lei G, Zhuang L, Gan B: Targeting Ferroptosis as a Vulnerability in Cancer. Nature Reviews Cancer 2022, 22: 381-396.

[181] Luo L, Wang H, Tian W, Li X, Zhu Z, Huang R, et al.: Targeting Ferroptosis-based Cancer Therapy Using Nanomaterials: Strategies and Applications. Theranostics 2021, 11: 9937-9952.

[182] Ensoy M, Ozturk BI, Cansaran-Duman D, Yilmazer A: Inducing Ferroptosis via Nanomaterials: A Novel and Effective Route in Cancer Therapy. Journal of Physics: Materials 2024, 7: 032003.