Advanced drug delivery platforms target cancer stem cells

Abstract

Cancer stem cells (CSCs) are a major challenge in cancer therapy. Stem cell-like cells form a unique subpopulation within many tumors, which govern the degree of malignancy by promoting metastasis, recurrence, heterogeneity, and resistance to drug and radiation. Furthermore, these cells can persist in patients even after undergoing multiple cycles of conventional cancer therapy via dormancy, where they no longer dividing but remain active. These may cause cancer recurrence at any time, even years after a supposed cure, and remain invisible to the immune system. Targeting specific surface markers, signaling pathways and tumor microenvironment, which all have a significant effect on CSC function and maintenance, could help to eradicate CSCs and improve patient survival. Combinations of traditional therapies with nano-based drug delivery systems can efficiently target CSCs. Considering the biology and properties of CSCs, we classify recent approaches involving nanoparticle engineering, extracellular matrix modulation, cocktail strategies, multi-stage therapy, CSC defanging, Trojan horse systems, targeted therapy and organelle targeting. We highlight the most recent advances in nanocarrier design and drug delivery technologies to target CSCs, combined with conventional treatment in preclinical and clinical trials. The prospects of these approaches for CSCs elimination and recurrent cancer treatment are discussed.

Keywords

Cancer stem cells / CSC biology / Recurrent cancer / Drug delivery systems / Engineered nano-carriers

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

RJE was supported by Tabriz University of Medical Sciences, grant number 65364.

References

[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA: Cancer J Clin 2022;72( 1):7-33.

[2] Zeng X, Liu C, Yao J, Wan H, Wan G, Li Y, et al. Breast cancer stem cells, heterogeneity, targeting therapies and therapeutic implications. Pharmacol Res 2021; 163:105320.

[3] Zuccherato LW, Machado CMT, Magalhães WCS, Martins PR, Campos LS, Braga LC, et al. Cervical cancer stem-like cell transcriptome profiles predict response to chemoradiotherapy. Front Oncol 2021; 11:639339.

[4] Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Targeted Ther 2020; 5(1):8.

[5] Batlle E, Clevers H. Cancer stem cells revisited. Nat Med 2017; 23(10):1124-34.

[6] Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell 2012; 10(6):717-28.

[7] Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. Int J Biochem Cell Biol 2012; 44(12):2144-51.

[8] Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA 2012; 109(8):2784-9.

[9] Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA 2013; 110(3):972-7.

[10] Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget 2017; 8(23):38022-43.

[11] Asghari F, Khademi R, Esmaeili Ranjbar F, Veisi Malekshahi Z, Faridi Majidi R. Application of nanotechnology in targeting of cancer stem cells: A review. Int J Stem Cells 2019; 12(2):227-39.

[12] Dadashi H, Eskandani M, Roshangar L, Sharifi-Azad M, Shahpouri M, Cho WC, et al. Remotely-controlled hydrogel platforms for recurrent cancer therapy. J Drug Delivery Sci Tech 2023; 82:104354.

[13] Zhao Y, Alakhova DY, Kabanov AV. Can nanomedicines kill cancer stem cells? Adv Drug Deliv Rev 2013; 65(13): 1763-1783.

[14] Kemp JA, Kwon YJ. Cancer nanotechnology: current status and perspectives. Nano Converg 2021; 8(1):34.

[15] Azizi M, Jahanban-Esfahlan R, Samadian H, Hamidi M, Seidi K, Dolatshahi-Pirouz A, et al. Multifunctional nanostructures: intelligent design to overcome biological barriers. Mat Today Bio 2023; 20:100672.

[16] Dianat-Moghadam H, Heydarifard M, Jahanban-Esfahlan R, Panahi Y, Hamishehkar H, Pouremamali F, et al. Cancer stem cells-emanated therapy resistance: implications for liposomal drug delivery systems. J Control Release 2018; 288:62-83.

[17] Doustmihan A, Fathi M, Mazloomi M, Salemi A, Hamblin MR. Jahanban-Esfahlan R. Molecular targets, therapeutic agents and multitasking nanoparticles to deal with cancer stem cells: A narrative review. J Control Release 2023; 363:57-83.

[18] Choudhury H, Gorain B, Pandey M, Nirmal J, Kesharwani P. Surface engineering of nanoparticles for imparting multifunctionality. In: Kesharwani P, Singh KK, Nanoparticle therapeutics. United States, Cambridge, Massachusetts: Academic Press; 2022. p. 181-210.

[19] Massoumi B, Abbasian M, Khalilzadeh B, Jahanban-Esfahlan R, Samadian H, Derakhshankhah H, et al. Electrically conductive nanofibers composed of chitosan-grafted polythiophene and poly (ε-caprolactone) as tissue engineering scaffold. Fibers Polymers 2021; 22(1):49-58.

[20] Xu X, Zhou T, Wei X, Jiang X, Cao J. Application of mPEG-CS-cRGD/bmi-1RNAi-PTX nanoparticles in suppression of laryngeal cancer by targeting cancer stem cells. Drug Deliv 2023; 30(1):2180112.

[21] Chen B, Dai W, He B, Zhang H, Wang X, Wang Y, et al. Current multistage drug delivery systems based on the tumor microenvironment. Theranostics 2017; 7(3):538-58.

[22] He B, Sui X, Yu B, Wang S, Shen Y, Cong H. Recent advances in drug delivery systems for enhancing drug penetration into tumors. Drug Deliv 2020; 27(1):1474-90.

[23] Wang Y, Sun T, Jiang C. Nanodrug delivery systems for ferroptosis-based cancer therapy. J Control Release 2022; 344:289-301.

[24] 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; 160:281-96.

[25] Eskandari A, Suntharalingam K. A reactive oxygen species-generating, cancer stem cell-potent manganese(ii) complex and its encapsulation into polymeric nanoparticles. Chem Sci 2019; 10(33):7792-800.

[26] Xiao C, Li J, Wang X, Li S, Xu C, Zhang Z, et al. Hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals for cancer therapy. J Control Release 2023; 356:288-305.

[27] Baghban R, Roshangar L, Jahanban-Esfahlan R, Seidi K, Ebrahimi-Kalan A, Jaymand M, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Comm Signal 2020; 18(1):59

[28] Ma J, Dai L, Yu J, Cao H, Bao Y, Hu J, et al. Tumor microenvironment targeting system for glioma treatment via fusion cell membrane coating nanotechnology. Biomaterials 2023; 295:122026.

[29] Jahanban-Esfahlan R, Derakhshankhah H, Haghshenas B, Massoumi B, Abbasian M, Jaymand M. A bio-inspired magnetic natural hydrogel containing gelatin and alginate as a drug delivery system for cancer chemotherapy. Int J Biol Macromol 2020; 156:438-45.

[30] Derakhshankhah H, Jahanban-Esfahlan R, Vandghanooni S, Akbari-Nakhjavani S, Massoumi B, Haghshenas B, et al. A bio-inspired gelatin-based pH - and thermal-sensitive magnetic hydrogel for in vitro chemo/hyperthermia treatment of breast cancer cells. J Appl Polym Sci 2021; 138:50578.

[31] Massoumi B, Abbasian M, Jahanban-Esfahlan R, Motamedi S, Samadian H, Rezaei A, et al. PEGylated hollow pH-responsive polymeric nanocapsules for controlled drug delivery. J Polymer Int 2020; 69(5):519-27.

[32] Jahanban-Esfahlan R, Soleimani K, Derakhshankhah H, Haghshenas B, Rezaei A, Massoumi B, et al. Multi-stimuli-responsive magnetic hydrogel based on Tragacanth gum as a de novo nanosystem for targeted chemo/hyperthermia treatment of cancer. J Materials Res 2021; 36:858-69.

[33] Mahmudi H, Shahpouri M, Adili-Aghdam MA, Akbari M, Salemi A, Alimohammadvand S, et al. Self-activating chitosan-based nanoparticles for sphingosin-1 phosphate modulator delivery and selective tumor therapy. Int J Biol Macromol 2024; 272:132940.

[34] Shahpouri M, Adili-Aghdam MA, Mahmudi H, Ghiasvand S, Dadashi H, Salemi A, et al. Dual-stage acting dendrimeric nanoparticle for deepened chemotherapeutic drug delivery to tumor cells. Adv Pharm Bullet 2024; 14(3):634-45.

[35] Soleimani K, Arkan E, Derakhshankhah H, Haghshenas B, Jahanban-Esfahlan R, Jaymand M. A novel bioreducible and pH -responsive magnetic nanohydrogel based on $\beta$-cyclodextrin for chemo/hyperthermia therapy of cancer. Carbohydrate Polymers 2021; 252:117229.

[36] Feng Q, Chen J, Huang J, Li X, Liu X, Xiao C, et al. A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3. J Control Release 2023; 363:349-60.

[37] Eskandani M, Derakhshankhah H, Jahanban-Esfahlan R, Jaymand M. Folate-conjugated pH- and redox-responsive magnetic hydrogel based on tragacanth gum for "smart" chemo/hyperthermia treatment of cancerous cells. J Drug Delivery Sci Technol 2023; 84:104449.

[38] Abed HF, Abuwatfa WH, Husseini GA. Redox-responsive drug delivery systems: A chemical perspective. Nanomaterials (Basel) 2022; 12(18):3183.

[39] Wang Z, Sun M, Li W, Fan L, Zhou Y, Hu Z. A novel CD133-and EpCAM-targeted liposome with redox-responsive properties capable of synergistically eliminating liver cancer stem cells. Front Chem 2020; 8:649.

[40] Yang Z, Sun N, Cheng R, Zhao C, Liu Z, Li X, et al. pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells. Biomaterials 2017; 147:53-67.

[41] Gu HF, Ren F, Mao XY, Du M. Mineralized and GSH-responsive hyaluronic acid based nano-carriers for potentiating repressive effects of sulforaphane on breast cancer stem cells-like properties. Carbohydr Polym 2021; 269:118294.

[42] Chen H, Guo Q, Chu Y, Li C, Zhang Y, Liu P, et al. Smart hypoxia-responsive transformable and charge-reversible nanoparticles for the deep penetration and tumor microenvironment modulation of pancreatic cancer. Biomaterials 2022; 287:121599.

[43] Yang H, Wang Q Li Z, Li F, Wu D, Fan M, et al. Hydrophobicity-adaptive nanogels for programmed anticancer drug delivery. Nano Letters 2018; 18(12):7909-18.

[44] Wijewantha N, Sane S, Eikanger M, Antony RM, Potts RA, Lang L, et al. Enhancing anti-tumorigenic efficacy of eugenol in human colon cancer cells using enzyme-responsive nanoparticles. Cancers (Basel) 2023; 15(4):1145.

[45] Yamasaki A, Yanai K, Onishi H. Hypoxia and pancreatic ductal adenocarcinoma. Cancer Letters 2020; 484:9-15.

[46] Mahmudi H, Adili-Aghdam MA, Shahpouri M, Jaymand M, Amoozgar Z, Jahanban-Esfahlan R. Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease. Front Oncol 2022; 12:1054029.

[47] Confeld MI, Mamnoon B, Feng L, Jensen-Smith H, Ray P, Froberg J, et al. Targeting the tumor core: hypoxia-responsive nanoparticles for the delivery of chemotherapy to pancreatic tumors. Mol Pharm 2020; 17(8):2849-63.

[48] Zhang Z, Deng Q, Xiao C, Li Z, Yang X. Rational design of nanotherapeutics based on the five features principle for potent elimination of cancer stem cells. Acc Chem Res 2022; 55(4):526-36.

[49] Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 2011; 278(1):16-27.

[50] Kong L, Sui GY, Guo RB, Cao HM, Yu Y, Liu Y, et al.A multi-strategy liposome targeting hepatocellular carcinoma cells and stem cells enhances the chemotherapy effect of doxorubicin in hepatocellular carcinoma. J Drug Delivery Sci Technol 2023; 81:104188.

[51] Wang Q, Liu F, Wang L, Xie C, Wu P, Du S, et al. Enhanced and prolonged antitumor effect of salinomycin-loaded gelatinase-responsive nanoparticles via targeted drug delivery and inhibition of cervical cancer stem cells. Int J Nanomed 2020; 15:1283-95.

[52] Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Res 2006; 66(9):4553-7.

[53] Tang L, Mei Y, Shen Y, He S, Xiao Q Yin Y, et al. Nanoparticle-mediated targeted drug delivery to remodel tumor microenvironment for cancer therapy. Int J Nanomed 2021; 16:5811-29.

[54] Jiang Y, Zhang H, Wang J, Liu Y, Luo T, Hua H. Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy. J Hematol Oncol 2022; 15(1):34.

[55] Omrani M, Beyrampour-Basmenj H, Jahanban-Esfahlan R, Talebi M, Raeisi M, Serej ZA, et al. Global trend in exosome isolation and application: an update concept in management of diseases. Mol Cell Biochem 2024; 479(3):679-91.

[56] Song K, Chen J, Ding J, Xu H, Xu H, Qin Z. Hyperbaric oxygen suppresses stemness-associated properties and Nanog and oncostatin M expression, but upregulates $\beta$-catenin in orthotopic glioma models. J Int Med Res 2020; 48(3):300060519872898.

[57] Liu X, Ye N, Xiao C, Wang X, Li S, Deng Y, et al. Hyperbaric oxygen regulates tumor microenvironment and boosts commercialized nanomedicine delivery for potent eradication of cancer stem-like cells. Nano Today 2021; 40:101248.

[58] Wang X, Ye N, Xu C, Xiao C, Zhang Z, Deng Q, et al. Hyperbaric oxygen regulates tumor mechanics and augments abraxane and gemcitabine antitumor effects against pancreatic ductal adenocarcinoma by inhibiting cancer-associated fibroblasts. Nano Today 2022; 44:101458.

[59] Wang C, Wang H, Yang H, Xu C, Wang Q, Li Z, et al. Targeting cancer-associated fibroblasts with hydroxyethyl starch nanomedicine boosts cancer therapy. Nano Res 2023; 16:7323-36.

[60] Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer 2021; 20(1):131.

[61] Pradhan R, Paul S, Das B, Sinha S, Dash SR, Mandal M, et al. Resveratrol nanoparticle attenuates metastasis and angiogenesis by deregulating inflammatory cytokines through inhibition of CAFs in oral cancer by CXCL-12/IL-6-dependent pathway. J Nutr Biochem 2023; 113:109257.

[62] Rasouli R, Paun RA, Tabrizian M. Sonoprinting nanoparticles on cellular spheroids via surface acoustic waves for enhanced nanotherapeutics delivery. Lab Chip 2023; 23(8):2091-105.

[63] Wang C, Wang Q, Wang H, Li Z, Chen J, Zhang Z, et al. Hydroxyethyl starch-folic acid conjugates stabilized theranostic nanoparticles for cancer therapy. J Control Release 2023; 353:391-410.

[64] Herheliuk T, Perepelytsina O, Ugnivenko A, Ostapchenko L, Sydorenko M. Investigation of multicellular tumor spheroids enriched for a cancer stem cell phenotype. Stem Cell Investig 2019; 6:21.

[65] Gao Y, Tang M, Leung E, Svirskis D, Shelling A, Wu Z. Dual or multiple drug loaded nanoparticles to target breast cancer stem cells. RSC Adv 2020; 10(32):19089-105.

[66] Gong J, Shi T, Liu J, Pei Z, Liu J, Ren X, et al. Dual-drug codelivery nanosystems: an emerging approach for overcoming cancer multidrug resistance. Biomed Pharmacother 2023; 161:114505.

[67] Shen S, Xu X, Lin S, Zhang Y, Liu H, Zhang C, et al. A nanotherapeutic strategy to overcome chemotherapeutic resistance of cancer stem-like cells. Nat Nanotechnol 2021; 16(1):104-13.

[68] Pan Y, Zhou S, Li Y, Parshad B, Li W, Haag R. Novel dendritic polyglycerol-conjugated, mesoporous silica-based targeting nanocarriers for co-delivery of doxorubicin and tariquidar to overcome multidrug resistance in breast cancer stem cells. J Control Release 2021; 330:1106-17.

[69] El-Sahli S, Hua K, Sulaiman A, Chambers J, Li L, Farah E, et al. A triple-drug nanotherapy to target breast cancer cells, cancer stem cells, and tumor vasculature. Cell Death Dis 2021; 12(1):8.

[70] Qi D, Liu Y, Li J, Huang JH, Hu X, Wu E. Salinomycin as a potent anticancer stem cell agent: State of the art and future directions. Med Res Rev 2022; 42(3):1037-63.

[71] Basu SM, Yadava SK, Singh R, Giri J. Lipid nanocapsules co-encapsulating paclitaxel and salinomycin for eradicating breast cancer and cancer stem cells. Colloids Surf B Biointerfaces 2021; 204:111775.

[72] Zhao D, Hu C, Fu Q, Lv H. Combined chemotherapy for triple negative breast cancer treatment by paclitaxel and niclosamide nanocrystals loaded thermosensitive hydrogel. Eur J Pharm Sci 2021; 167:105992.

[73] Cámara-Sánchez P, Díaz-Riascos ZV, García-Aranda N, Gener P, Seras-Franzoso J, Giani-Alonso M, et al. Selectively targeting breast cancer stem cells by 8-quinolinol and niclosamide. Int J Mol Sci 2022; 23(19):11760.

[74] Tefas LR, Toma I, Sesarman A, Banciu M, Jurj A, Berindan-Neagoe I, et al. Co-delivery of gemcitabine and salinomycin in PEGylated liposomes for enhanced anticancer efficacy against colorectal cancer. J Liposome Res 2023; 33(3):234-50.

[75] Anees M, Mehrotra N, Tiwari S, Kumar D, Kharbanda S, Singh H. Polylactic acid based biodegradable hybrid block copolymeric nanoparticle mediated co-delivery of salinomycin and doxorubicin for cancer therapy. Int J Pharm 2023; 635:122779.

[76] Narayanaswamy R, Torchilin VP. Targeted delivery of combination therapeutics using monoclonal antibody 2C5-modified immunoliposomes for cancer therapy. Pharm Res 2021; 38(3):429-50.

[77] Zhao Y, Wang K, Zheng Y, Zeng X, Lim YC, Liu T. Co-delivery of salinomycin and curcumin for cancer stem cell treatment by inhibition of cell proliferation, cell cycle arrest, and epithelial-mesenchymal transition. Front Chem 2020; 8:601649.

[78] Song X, Zhang R, Liang C, Chen Q, Gong H, Liu Z. Nano-assemblies of J-aggregates based on a NIR dye as a multifunctional drug carrier for combination cancer therapy. Biomaterials 2015; 57:84-92.

[79] Wang J, Liu N, Su Q, Lv Y, Yang C, Zhan H. Green synthesis of gold nanoparticles and study of their inhibitory effect on bulk cancer cells and cancer stem cells in breast carcinoma. Nanomaterials 2022; 12(19):3324.

[80] Vankayala R, Lin CC, Kalluru P, Chiang CS, Hwang KC. Gold nanoshells-mediated bimodal photodynamic and photothermal cancer treatment using ultra-low doses of near infra-red light. Biomaterial 2014; 35(21):5527-38.

[81] Chang X, Zhang M, Wang C, Zhang J, Wu H, Yang S. Graphene oxide /BaHoF5 / PEG nanocomposite for dual-modal imaging and heat shock protein inhibitor-sensitized tumor photothermal therapy. Carbon 2020; 158:372-85.

[82] Mu X, Chang Y, Bao Y, Cui A, Zhong X, Cooper GB, et al.Core-satellite nanoreactors based on cationic photosensitizer modified hollow CuS nanocage for ROS diffusion enhanced phototherapy of hypoxic tumor. Biomater Adv 2023; 145:213263.

[83] Zhao C, Han X, Wang S, Pan Z, Tang X, Jiang Z. Violet phosphorus nanosheet: A biocompatible and stable platform for stimuli-responsive multimodal cancer phototherapy. Adv Healthc Mater 2023; 12(3):e2201995.

[84] Li Y, Liu G, Ma J, Lin J, Lin H, Su G, et al. Chemotherapeutic drug-photothermal agent co-self-assembling nanoparticles for near-infrared fluorescence and photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy. J Control Release 2017; 258:95-107.

[85] Ding M, Zhang W, Zhang X, Shang H, Zhang A. A multifunctional FA/rGO/MSN-IR820 nanotherapeutic platform for photodynamic/photothermal therapy of tumor. Mater Lett 2023; 331:133508.

[86] Barcelos JM, Hayasaki TG, de Santana RC, Lima EM, Mendanha SA, Bakuzis AF. Photothermal properties of IR-780-based nanoparticles depend on nanocarrier design: A comparative study on synthetic liposomes and cell membrane and hybrid biomimetic vesicles. Pharmaceutics 2023; 15(2):444.

[87] Yu J, Wang L, Xie X, Zhu W, Lei Z, Lv L, et al. Multifunctional nanoparticles codelivering doxorubicin and amorphous calcium carbonate preloaded with indocyanine green for enhanced chemo-photothermal cancer therapy. Int J Nanomed 2023; 18:323-37.

[88] Shang Q, Zhou S, Zhou Z, Jiang Y, Luan Y. Dual cancer stem cell manipulation to enhance phototherapy against tumor progression and metastasis. J Control Release 2021; 340:282-91.

[89] Zhu X, Li L, Tang J, Yang C, Yu H, Liu K, et al. Cascade-responsive nano-assembly for efficient photothermal-chemo synergistic inhibition of tumor metastasis by targeting cancer stem cells. Biomaterials 2022; 280:121305.

[90] Jia Y, Sun J, Yang J, Chen C, Zhang Z, Yang K, et al. Tumor microenvironment-responsive nanoherb delivery system for synergistically inhibition of cancer scem cells. ACS Appl Mater Interfaces 2023; 15(13):16329-42.

[91] Liu S, Zhang T, Li S, Wu Q, Wang K, Xu X, et al. Biomimetic nsnobomb for synergistic therapy with inhibition of cancer stem cells. Small 2023; 19(12):e2206503.

[92] Ning S, Zhang T, Lyu M, Lam JWY, Zhu D, Huang Q et al. A type I AIE photosensitiser-loaded biomimetic nanosystem allowing precise depletion of cancer stem cells and prevention of cancer recurrence after radiotherapy. Biomaterials 2023; 295:122034.

[93] Dash SR, Das B, Das C, Sinha S, Paul S, Pradhan R, et al. Near-infrared enhances antiangiogenic potentiality of quinacrine-gold hybrid nanoparticles in breast cancer stem cells via deregulation of HSP-70/TGF- $\beta$. Nanomedicine (Lond) 2023; 18(1):19-33.

[94] Li H, Yan W, Suo X, Peng H, Yang X, Li Z, et al. Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy. Biomaterials 2019; 200:1-14.

[95] Yu X, Ma H, Xu G, Liu Z. Radiotherapy assisted with biomaterials to trigger antitumor immunity. Chinese Chem Lett 2022; 33(9):4169-74.

[96] Huang T, Lee JS, Klibanov AL, He J. Molecular radiotherapy with 177Lu-immunoliposomes induces cytotoxicity in mesothelioma cancer stem cells in vitro. Int J Mol Sci 2022; 23(7):3914.

[97] Salah M, Akasaka H, Shimizu Y, Morita K, Nishimura Y, Kubota H, et al. Reactive oxygen species-inducing titanium peroxide nanoparticles as promising radiosensitizers for eliminating pancreatic cancer stem cells. J Exp Clin Cancer Res 2022; 41(1):146.

[98] Lee J, Davaa E, Jiang Y, Shin KJ, Kim MH, An H, et al. Pheophorbide A and SN38 conjugated hyaluronan nanoparticles for photodynamic- and cascadic chemotherapy of cancer stem-like ovarian cancer. Carbohydrate Polymers 2022; 289:119455.

[99] Dash SR, Chatterjee S, Sinha S, Das B, Paul S, Pradhan R, et al. NIR irradiation enhances the apoptotic potentiality of quinacrine-gold hybrid nanoparticles by modulation of HSP-70 in oral cancer stem cells. Nanomed: Nanotechnol, Biol Med 2022; 40:102502.

[100] Fernandes S, Fernandez T, Metze S, Balakrishnan PB, Mai BT, Conteh J, et al. Magnetic nanoparticle-based hyperthermia mediates drug delivery and impairs the tumorigenic capacity of quiescent colorectal cancer stem cells. ACS Appl Mater Interfaces 2021; 13(14):15959-72.

[101] Kumar VE, Nambiar R, De Souza C, Nguyen A, Chien J, Lam KS. Targeting epigenetic modifiers of tumor plasticity and cancer stem cell behavior. Cells 2022; 11(9):1403.

[102] Keyvani-Ghamsari S, Khorsandi K, Rasul A, Zaman MK. Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin Epigenetics 2021; 13(1):120.

[103] Naik PP, Panigrahi S, Parida R, Praharaj PP, Bhol CS, Patil S, et al. Metabostemness in cancer: linking metaboloepigenetics and mitophagy in remodeling cancer stem cells. Stem Cell Rev Rep 2022; 18(1):198-213.

[104] Wainwright EN, Scaffidi P. Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity. Trends Cancer 2017; 3(5):372-86.

[105] Li SY, Sun R, Wang HX, Shen S, Liu Y, Du XJ, et al. Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells. J Control Release 2015; 205:7-14.

[106] Pan Y, Ma X, Liu C, Xing J, Zhou S, Parshad B, et al. Retinoic acid-loaded dendritic polyglycerol-conjugated gold nanostars for targeted photothermal therapy in breast cancer stem cells. ACS Nano 2021; 15(9):15069-84.

[107] Chu Y, Luo Y, Su B, Li C, Guo Q, Zhang Y, et al. A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy. Acta Pharm Sin B 2023; 13(1):298-314.

[108] Xu C, Li S, Chen J, Wang H, Li Z, Deng Q, et al. Doxorubicin and erastin co-loaded hydroxyethyl starch-polycaprolactone nanoparticles for synergistic cancer therapy. J Control Release 2023; 356:256-71.

[109] Lee KS, Choi JS, Cho YW. Reprogramming of cancer stem cells into non-tumorigenic cells using stem cell exosomes for cancer therapy. Biochem Biophys Res Commun 2019; 512(3):511-16.

[110] Singh D, Singh P, Pradhan A, Srivastava R, Sahoo SK. Reprogramming cancer stem-like cells with nanoforskolin enhances the efficacy of paclitaxel in targeting breast cancer. ACS Appl Bio Mater 2021; 4(4):3670-85.

[111] Rezaei R, Baghaei K, Amani D, Piccin A, Hashemi SM, Asadzadeh Aghdaei H, et al. Exosome-mediated delivery of functionally active miRNA-375-3p mimic regulate epithelial mesenchymal transition (EMT) of colon cancer cells. Life Sci 2021; 269:119035.

[112] Shen S, Li T, Fan J, Shao Q, Dong H, Xu X, et al. Lipid-polymer hybrid nanoparticle with cell-distinct drug release for treatment of stemness-derived resistant tumor. Acta Pharm Sin B 2023; 13(3):1262-73.

[113] Wang H, Agarwal P, Zhao S, Xu RX, Yu J, Lu X, et al. Hyaluronic acid-decorated dual responsive nanoparticles of Pluronic F127, PLGA, and chitosan for targeted co-delivery of doxorubicin and irinotecan to eliminate cancer stem-like cells. Biomaterials 2015; 72:74-89.

[114] Xia Q, Zhang Y, Li Z, Hou X, Feng N. Red blood cell membrane-camouflaged nanoparticles: a novel drug delivery system for antitumor application. Acta Pharm Sin B 2019; 9(4):675-89.

[115] Fang RH, Jiang Y, Fang JC, Zhang L. Cell membrane-derived nanomaterials for biomedical applications. Biomaterials 2017; 128:69-83.

[116] Vijayan V, Uthaman S, Park IK. Cell membrane coated nanoparticles: an emerging biomimetic nanoplatform for targeted bioimaging and therapy. Adv Exp Med Biol 2018; 1064:45-59.

[117] Imran M, Jha LA, Hasan N, Shrestha J, Pangeni R, Parvez N, et al. "Nanodecoys"-Future of drug delivery by encapsulating nanoparticles in natural cell membranes. Int J Pharmaceut 2022; 621:121790.

[118] Li R, He Y, Zhang S, Qin J, Wang J. Cell membrane-based nanoparticles: a new biomimetic platform for tumor diagnosis and treatment. Acta Pharm Sin B 2018; 8(1):14-22.

[119] Zhao Q, Sun XY, Wu B, Shang Y, Huang X, Dong H, et al. Construction of biomimetic silver nanoparticles in the treatment of lymphoma. Mater Sci Eng C Mater Biol Appl 2021; 119:111648.

[120] Song M, Dong S, An X, Zhang W, Shen N, Li Y, et al. Erythrocyte-biomimetic nanosystems to improve antitumor effects of paclitaxel on epithelial cancers. J Control Release 2022; 345:744-54.

[121] Scioli MG, Terriaca S, Fiorelli E, Storti G, Fabbri G, Cervelli V, et al. Extracellular vesicles and cancer stem cells in tumor progression: new therapeutic perspectives. Int J Mol Sci 2021; 22(19):10572.

[122] Jurj A, Zanoaga O, Braicu C, Lazar V, Tomuleasa C, Irimie A, et al. A comprehensive picture of extracellular vesicles and their contents. Molecular transfer to cancer cells. Cancers (Basel) 2020; 12(2):298.

[123] Su C, Zhang J, Yarden Y, Fu L. The key roles of cancer stem cell-derived extracellular vesicles. Signal Transduct Target Ther 2021; 6(1):109.

[124] Lindoso RS, Collino F, Camussi G. Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells. Oncotarget 2015; 6(10):7959-69.

[125] Lin MC, Chen SY, He PL, Herschman H, Li HJ. PGE( 2) /EP(4) antagonism enhances tumor chemosensitivity by inducing extracellular vesicle-mediated clearance of cancer stem cells. Int J Cancer 2018; 143(6):1440-55.

[126] Li X, Li X, Zhang B, He B. The role of cancer stem cell-derived exosomes in cancer progression. Stem Cells Int 2022; 2022:9133658.

[127] Liu K, Gao X, Kang B, Liu Y, Wang D, Wang Y. The role of tumor stem cell exosomes in cancer invasion and metastasis. Front Oncol 2022; 12:836548.

[128] Batrakova EV, Kim MS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release 2015; 219:396-405.

[129] Wang J, Zheng Y, Zhao M. Exosome-based cancer therapy: implication for targeting cancer stem cells. Front Pharmacol 2017; 7:533.

[130] Naseri Z, Oskuee RK, Forouzandeh-Moghadam M, Jaafari MR. Delivery of LNA-antimiR-142-3p by mesenchymal stem cells-derived exosomes to breast cancer stem cells reduces tumorigenicity. Stem Cell Rev Rep 2020; 16(3):541-56.

[131] Hu Y, Liu H, Xiao X, Yu Q, Deng R, Hua L, et al. Bone marrow mesenchymal stem cell-derived exosomes inhibit triple-negative breast cancer cell stemness and metastasis via an ALKBH5-dependent mechanism. Cancers (Basel) 2022; 14(24):6059.

[132] Yang YS, Jia XZ, Lu QY, Cai SL, Huang XT, Yang SH, et al. Exosomal DEK removes chemoradiotherapy resistance by triggering quiescence exit of breast cancer stem cells. Oncogene 2022; 41(18):2624-37.

[133] Lu B, Huang X, Mo J, Zhao W. Drug delivery using nanoparticles for cancer stem-like cell targeting. Front Pharmacol 2016; 7:84.

[134] Chen H, Jiang Y, Li X. Adriamycin-loaded exosome with anti-CD20 aptamers selectively suppresses human CD20+ melanoma stem cells. Skin Res Technol 2023; 29(1): e13259.

[135] Ren K, He J, Qiu Y, Xu Z, Wang X, Li J, et al. A neutrophil-mediated carrier regulates tumor stemness by inhibiting autophagy to prevent postoperative triple-negative breast cancer recurrence and metastasis. Acta biomaterialia 2022; 145:185-99.

[136] Wang W, Wu F, Mohammadniaei M, Zhang M, Li Y, Sun Y, et al. Genetically edited T-cell membrane coated AIEgen nanoparticles effectively prevents glioblastoma recurrence. Biomaterials 2023; 293:121981.

[137] Crupi MJF, Bell JC, Singaravelu R. Concise review: targeting cancer stem cells and their supporting niche using oncolytic viruses. Stem Cells 2019; 37(6):716-23.

[138] Heidbuechel JPW, Engeland CE. Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies. J Hematol Oncol 2021; 14(1):63.

[139] Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, et al. Glioblastoma multiforme (GBM): an overview of current therapies and mechanisms of resistance. Pharmacol Res 2021; 171:105780.

[140] MlakarJ, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika virus associated with microcephaly. New Engl J Med 2016; 374(10):951-8.

[141] Zhu Z, Mesci P, Bernatchez JA, Gimple RC, Wang X, Schafer ST, et al. Zika virus targets glioblastoma stem cells through a SOX2-integrin $\alpha \mathrm{v} \beta 5$ axis. Cell Stem Cell 2020; 26(2):187-204 e10.

[142] Nair S, Mazzoccoli L, Jash A, Govero J, Bais SS, Hu T, et al. Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade. JCI Insight 2021; 6(1):e144619.

[143] Masoumeh Sharifi-Azad MF, William CCho, Barzegari Abolfazl, Dadashi Hamed, Dadashpour Mehdi, Jahanban-Esfahlan Rana. Recent advances in targeted drug delivery systems for resistant colorectal cancer. Cancer Cell Int 2022; 22(196):1-21.

[144] Majidinia M, Aghazadeh J, Jahanban-Esfahlani R, Yousefi B. The roles of wnt/beta-catenin pathway in tissue development and regenerative medicine. J Cell Physiol 2018; 233(8):5598-612.

[145] Majidinia M, Darband SG, Kaviani M, Nabavi SM, Jahanban-Esfahlan R, Yousefi B. Cross-regulation between Notch signaling pathway and miRNA machinery in cancer. DNA Repair (Amst) 2018;66-67:30-41.

[146] Seidi K, Jahanban-Esfahlan R, Zarghami N. Tumor rim cells: from resistance to vascular targeting agents to complete tumor ablation. Tumour Biol 2017; 39(3): 1010428317691001.

[147] Clara JA, Monge C, Yang Y, Takebe N. Targeting signalling pathways and the immune microenvironment of cancer stem cells-a clinical update. Nat Rev Clin Oncol 2020; 17(4):204-32.

[148] Althobiti M, El Ansari R, Aleskandarany M, Joseph C, Toss MS, Green AR, et al. The prognostic significance of ALDH1A1 expression in early invasive breast cancer. Histopathology 2020; 77(3):437-48.

[149] Zhao W, Li Y, Zhang X. Stemness-related markers in cancer. Cancer Transl Med 2017; 3(3):87-95.

[150] Iżycka N, Zaborowski MP, Ciecierski Ł, Jaz K, Szubert S, Miedziarek C, et al. Cancer stem cell markers-clinical relevance and prognostic value in high-grade serous ovarian cancer (HGSOC) based on the cancer genome atlas analysis. Int J Mol Sci 2023; 24(16):12746.

[151] Peitzsch C, Nathansen J, Schniewind SI, Schwarz F, Dubrovska A. Cancer stem cells in head and neck squamous cell carcinoma: identification, characterization and clinical implications. Cancers 2019; 11(5):616.

[152] Ertas YN, Abedi Dorcheh K, Akbari A, Jabbari E. Nanoparticles for targeted drug delivery to cancer stem cells: a review of recent advances. Nanomaterials (Basel) 2021; 11(7):1755.

[153] Zhang H, Brown RL, Wei Y, Zhao P, Liu S, Liu X, et al. CD44 splice isoform switching determines breast cancer stem cell state. Genes Dev 2019; 33(3-4):166-79.

[154] Hassn Mesrati M, Syafruddin SE, Mohtar MA, Syahir A. CD44: A multifunctional mediator of cancer progression. Biomolecules 2021; 11(12):1850.

[155] Gheybi E, Asoodeh A, Amani J. Preparation of chitosan nanoparticle containing recombinant CD44v antigen and evaluation of its immunization capacity against breast cancer in BALB/c mice. BMC Cancer 2023; 23(1):134.

[156] Almoustafa HA, Alshawsh MA, Al-Suede FSR, Alshehade SA, Abdul Majid AMS, Chik Z. The chemotherapeutic efficacy of hyaluronic acid coated polymeric nanoparticles against breast cancer metastasis in female NCr-Nu/Nu nude mice. Polymers (Basel) 2023; 15(2):284.

[157] Lee JS, Park E, Oh H, Choi WI, Koo H. Levan nanoparticles with intrinsic CD44-targeting ability for tumor-targeted drug delivery. Int J Biol Macromol 2023; 234:123634.

[158] Ren XH, Han D, He XY, Guo T, Chen XS, Pang X, et al. Multi-targeting nano-systems targeting heterogeneous cancer cells for therapeutics and biomarker detection. Adv Healthcare Materials 2023; 12(4):2202155.

[159] Zhang Y, Wang Z, Hu Q, Luo H, Lu B, Gao Y, et al. 3D Bioprinted GelMA-nanoclay hydrogels induce colorectal cancer stem cells through activating wnt/ $\beta$-catenin signaling. Small 2022; 18(18):2200364.

[160] Mansour W, El Fedawy SF, Atta SA, Zarie RM, Fouad NTA, Maher S, et al. Targeted therapy for HCC using dumbbell-like nanoparticles conjugated to monoclonal antibodies against VEGF and cancer stem cell receptors in mice. Cancer Nanotechnol 2023; 14(1):14.

[161] Petersburg J, Vallera DA, Wagner CR. Eradication of heterogeneous tumors by T cells targeted with combination bispecific chemically self-assembled nanorings. Mol Cancer Ther 2023; 22(3):371-80.

[162] Pandey S, Lee M, Lim J, Park S, Choung YH, Kim JE, et al. SMO-CRISPR-mediated apoptosis in CD133-targeted cancer stem cells and tumor growth inhibition. J Control Release 2023; 357:94-108.

[163] Koh EY, You JE, Jung SH, Kim PH. Biological functions and identification of novel biomarker expressed on the surface of breast cancer-derived cancer stem cells via proteomic analysis. Mol Cells 2020; 43(4):384-96.

[164] Koh EY, Kim KS, Park HB, Kim JS, Kim PH. Active targeting of versatile nanocomplex using the novel biomarker of breast cancer stem cells. Int J Mol Sci 2022; 24(1):685.

[165] Raha D, Wilson TR, Peng J, Peterson D, Yue P, Evangelista M, et al. The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. Cancer Res 2014; 74(13):3579-90.

[166] Kuo YC, Wang LJ, Rajesh R. Targeting human brain cancer stem cells by curcumin-loaded nanoparticles grafted with anti-aldehyde dehydrogenase and sialic acid: colocalization of ALDH and CD44. Materials Sci Engineer: C 2019; 102:362-72.

[167] Abu-Serie MM, Abdelfattah EZA. Anti-metastatic breast cancer potential of novel nanocomplexes of diethyldithiocarbamate and green chemically synthesized iron oxide nanoparticles. Int J Pharm 2022; 627:122208.

[168] Abu-Serie MM. Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer. Front Pharmacol 2022; 13:1089667.

[169] Cui J, Li W, Bu W, Liu J, Chen X, Li X, et al. Folic acid-modified disulfiram/Zn-IRMOF3 nanoparticles for oral cancer therapy by inhibiting ALDH1A1+ cancer stem cells. Biomater Adv 2022; 139:213038.

[170] Abu-Serie MM, Abdelfattah EZA. A comparative study of smart nanoformulations of diethyldithiocarbamate with $\mathrm{Cu}_{4} \mathrm{O}_{3}$ nanoparticles or zinc oxide nanoparticles for efficient eradication of metastatic breast cancer. Sci Rep 2023; 13(1):3529.

[171] Jain V, Singh MP, Amaravadi RK. Recent advances in targeting autophagy in cancer. Trends Pharmacol Sci 2023; 44(5):290-302.

[172] Fauzi YR, Nakahata S, Chilmi S, Ichikawa T, Nueangphuet P, Yamaguchi R, et al. Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF- $\kappa$ b signaling pathway through abrogation of autophagic p 47 degradation in adult T-cell leukemia/lymphoma cells. PLoS One 2021; 16(8):e0256320.

[173] Sun R, Shen S, Zhang YJ, Xu CF, Cao ZT, Wen LP, et al. Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells. Biomaterials 2016; 103:44-55.

[174] Lu L, Shen X, Tao B, Lin C, Li K, Luo Z, et al. The nanoparticle-facilitated autophagy inhibition of cancer stem cells for improved chemotherapeutic effects on glioblastomas. J Mater Chem B 2019; 7(12):2054-62.

[175] Gao X, Jiang P, Liu L, et al. Zhang Q Liu Q Jiang S, Peglated-H1/pHGFK1 nanoparticles enhance anti-tumor effects of sorafenib by inhibition of drug-induced autophagy and stemness in renal cell carcinoma. J Exp Clin Cancer Res 2019; 38(1):362.

[176] Wu X, Sheng H, Zhao L, Jiang M, Lou H, Miao Y, et al. Co-loaded lapatinib/PAB by ferritin nanoparticles eliminated ECM-detached cluster cells via modulating EGFR in triple-negative breast cancer. Cell Death & Disease 2022; 13(6):557.

[177] Takahashi-Yanaga F, Kahn M. Targeting wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 2010; 16(12):3153-62.

[178] Wend P, Holland JD, Ziebold U, Birchmeier W. Wnt signaling in stem and cancer stem cells. Semin Cell Development Biol 2010; 21(8):855-63.

[179] Yao H, Ashihara E, Maekawa T. Targeting the Wnt /$\beta$-catenin signaling pathway in human cancers. Exp Opin Therapeut Targets 2011; 15(7):873-87.

[180] Mandal S, Arfuso F, Sethi G, Dharmarajan A, Warrier S. Encapsulated human mesenchymal stem cells (eMSCs) as a novel anti-cancer agent targeting breast cancer stem cells: development of 3D primed therapeutic MSCs. Int J Biochem Cell Biol 2019; 110:59-69.

[181] Shamsian A, Sepand MR, Javaheri Kachousangi M, Dara T, Ostad SN, Atyabi F, et al. Targeting tumorigenicity of breast cancer stem cells using SAHA/Wnt-b catenin antagonist loaded onto protein corona of gold nanoparticles. Int J Nanomed 2020; 15:4063-78.

[182] Li Y, Wang Z, Ajani JA, Song S. Drug resistance and cancer stem cells. Cell Commun Signal 2021; 19(1):19.

[183] Cui Y, Zhao M, Yang Y, Xu R, Tong L, Liang J, et al. Reversal of epithelial-mesenchymal transition and inhibition of tumor stemness of breast cancer cells through advanced combined chemotherapy. Acta biomaterialia 2022; 152:380-92.

[184] Zuo ZQ, Chen KG, Yu XY, Zhao G, Shen S, Cao ZT, et al. Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF- $\beta$ signaling pathway inhibition. Biomaterials 2016; 82:48-59.

[185] Lazer LM, Kesavan Y, Gor R, Ramachandran I, Pathak S, Narayan S, et al. Targeting colon cancer stem cells using novel doublecortin like kinase 1 antibody functionalized folic acid conjugated hesperetin encapsulated chitosan nanoparticles. Colloids Surf B Biointerfaces 2022; 217:112612.

[186] El-Houssiny AS, Kamel NA, Soliman AAF, El-Messieh SLA, Abd-El-Nour KN. Preparation and characterisation of gallic acid loaded carboxymethyl chitosan nanoparticles as drug delivery system for cancer treatment. Adv Natural Sci: Nanosci Nanotech 2022; 13(2):025002.

[187] Loh CY, Chai JY, Tang TF, wong wF, Sethi G, Shanmugam MK, et al. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells 2019; 8(10):1118.

[188] Wang Y, Ma S, Liu X, Wei Y, Xu H, Liang Z, et al. Hyaluronic acid mediated Fe₃O₄ nanocubes reversing the EMT through targeted cancer stem cell. Colloid Surfaces B: Biointerfaces 2023; 222:113071.

[189] Abel EV, Kim EJ, Wu J, Hynes M, Bednar F, Proctor E, et al. The notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLOS ONE 2014; 9(3):e91983.

[190] Ghanbari-Movahed M, Shiri Varnamkhasti B, Shourian M. Inhibiting Notch activity in breast cancer stem cells by functionalized gold nanoparticles with gamma-secretase inhibitor DAPT and vitamin C. Chem Papers 2022; 76(2):1157-70.

[191] Witte KE, Hertel O, Windmöller BA, Helweg LP, Höving AL, Knabbe C, et al. Nanopore sequencing reveals global transcriptome signatures of mitochondrial and ribosomal gene expressions in various human cancer stem-like cell populations. Cancers (Basel) 2021; 13(5):1136.

[192] Praharaj PP, Panigrahi DP, Bhol CS, Patra S, Mishra SR, Mahapatra KK, et al. Mitochondrial rewiring through mitophagy and mitochondrial biogenesis in cancer stem cells: A potential target for anti-CSC cancer therapy. Cancer Lett 2021; 498:217-28.

[193] Liang X, Xu S, Zhang J, Li J, Shen Q. Cascade amplifiers of intracellular reactive oxygen species based on mitochondria-targeted core-shell ZnO-TPP@D/H nanorods for breast cancer therapy. ACS Appl Mater Interfaces 2018; 10(45):38749-59.

[194] Cheng X, Feng D, Lv J, Cui X, Wang Y, Wang Q et al. Application prospects of triphenylphosphine-based mitochondria-targeted cancer therapy. Cancers (Basel) 2023; 15(3):666.

[195] Chang CM, Lan KL, Huang WS, Lee YJ, Lee TW, Chang CH, et al. ¹⁸⁸Re-liposome can induce mitochondrial autophagy and reverse drug resistance for ovarian cancer: from bench evidence to preliminary clinical proof-of-concept. Int J Mol Sci 2017; 18(5):903.

[196] Li Q, Huang Y. Mitochondrial targeted strategies and their application for cancer and other diseases treatment. J Pharmaceut Investig 2020; 50(3):271-93.

[197] Ozsvari B, Sotgia F, Lisanti MP.Exploiting mitochondrial targeting signal(s), TPP and bis-TPP, for eradicating cancer stem cells (CSCs). Aging (Albany NY) 2018; 10(2):229-40.

[198] Ba S, Qiao M, Jia L, Zhang J, Zhao X, Hu H, et al. Construction of hierarchical-targeting pH -sensitive liposomes to reverse chemotherapeutic resistance of cancer stem-like cells. Pharmaceutics 2021; 13(8):1205.

[199] Pan Y, Zhou S, Liu C, Ma X, Xing J, Parshad B, et al. Dendritic polyglycerol-conjugated gold nanostars for metabolism inhibition and targeted photothermal therapy in breast cancer stem cells. Adv Healthc Mater 2022; 11(8):e2102272.

[200] Wang J, Yang B, Lv C, Chen T, Sun L, Sun L, et al. Amino porphyrin-peptide assemblies induce ribosome damage and cancer stem cell inhibition for an enhanced photodynamic therapy. Biomaterials 2022; 289:121812.

[201] Liu D, Hong Y, Li Y, Hu C, Yip TC, Yu WK, et al. Targeted destruction of cancer stem cells using multifunctional magnetic nanoparticles that enable combined hyperthermia and chemotherapy. Theranostics 2020; 10(3):1181-96.

[202] Paholak HJ, Stevers NO, Chen H, Burnett JP, He M, Korkaya H, et al. Elimination of epithelial-like and mesenchymal-like breast cancer stem cells to inhibit metastasis following nanoparticle-mediated photothermal therapy. Biomaterials 2016; 104:145-57.

[203] Xie X, Jiang K, Li B, Hou S, Tang H, Shao B, et al. A small-molecule self-assembled nanodrug for combination therapy of photothermal-differentiation-chemotherapy of breast cancer stem cells. Biomaterials 2022; 286:121598.

[204] Tian J, Gu Y, Li Y, Liu T. CD 271 antibody-functionalized HGNs for targeted photothermal therapy of osteosarcoma stem cells. Nanotechnology 2020; 31(30):305707.

[205] Sun T, Yin YF, Jin HG, Liu HR, Tian WC. Exosomal microRNA-19b targets FBXW7 to promote colorectal cancer stem cell stemness and induce resistance to radiotherapy. Kaohsiung J Med Sci 2022; 38(2):108-19.

[206] Kunoh T, Shimura T, Kasai T, Matsumoto S, Mahmud H, Khayrani AC, et al. Use of DNA-generated gold nanoparticles to radiosensitize and eradicate radioresistant glioma stem cells. Nanotechnology 2019; 30(5):055101.

[207] Qian L, Liu F, Chu Y, Zhai Q Wei X, Shao J, et al. MicroRNA-200c nanoparticles sensitized gastric cancer cells to radiotherapy by regulating PD-L1 expression and EMT. Cancer Manag Res 2020; 12:12215-23.

[208] Liu L, Zhang Z, Zhou L, Hu L, Yin C, Qing D, et al. Cancer associated fibroblasts-derived exosomes contribute to radioresistance through promoting colorectal cancer stem cells phenotype. Exp Cell Res 2020; 391(2):111956.

[209] Lu SL, Wang YH, Liu GF, Wang L, Li Y, Guo ZY, et al. Graphene oxide nanoparticle-loaded ginsenoside Rg3 improves photodynamic therapy in inhibiting malignant progression and stemness of osteosarcoma. Front Mol Biosci 2021; 8:663089.

[210] Zhou J, Sun M, Jin S, Fan L, Zhu W, Sui X, et al. Combined using of paclitaxel and salinomycin active targeting nanostructured lipid carriers against non-small cell lung cancer and cancer stem cells. Drug Deliv 2019; 26(1):281-9.

[211] Chen F, Zeng Y, Qi X, Chen Y, Ge Z, Jiang Z, et al. Targeted salinomycin delivery with EGFR and CD133 aptamers based dual-ligand lipid-polymer nanoparticles to both osteosarcoma cells and cancer stem cells. Nanomedicine 2018; 14(7):2115-27.

[212] Li J, Xu W, Yuan X, Chen H, Song H, Wang B, et al. Polymer-lipid hybrid anti-HER2 nanoparticles for targeted salinomycin delivery to HER2-positive breast cancer stem cells and cancer cells. Int J Nanomed 2017; 12:6909-21.

[213] Jiang T, Xie L, Zhou S, Liu Y, Huang Y, Mei N, et al. Metformin and histone deacetylase inhibitor based anti-inflammatory nanoplatform for epithelial-mesenchymal transition suppression and metastatic tumor treatment. J Nanobiotechnol 2022; 20(1):394.

[214] Dianat-Moghadam H, Abbasspour-Ravasjani S, Hamishehkar H, Rahbarghazi R, Nouri M. LXR inhibitor SR9243-loaded immunoliposomes modulate lipid metabolism and stemness in colorectal cancer cells. Med Oncol 2023; 40(6):156.

[215] Yin X, Lu Y, Zou M, Wang L, Zhou X, Zhang Y, et al. Synthesis and characterization of salinomycin-loaded high-density lipoprotein and its effects on cervical cancer cells and cervical cancer stem cells. Int J Nanomed 2021; 16:6367-82.

[216] Passeri G, Vincent RA, Xiao Z, Northcote-Smith J, Suntharalingam K. Encapsulation and delivery of an osteosarcoma stem cell active gallium(III)-diflunisal complex using polymeric micelles. ChemMedChem 2023; 18(4):e202200599.

[217] Terai K, Bi D, Liu Z, Kimura K, Sanaat Z, Dolatkhah R, et al. A novel oncolytic herpes capable of cell-specific transcriptional targeting of CD 133 ± cancer cells induces significant tumor regression. Stem Cells 2018; 36(8):1154-69.

[218] Su Z, Liu D, Chen L, Zhang J, Ru L, Chen Z, et al. CD44-targeted magnetic nanoparticles kill head and neck squamous cell carcinoma stem cells in an alternating magnetic field. Int J Nanomed 2019; 14:7549-60.

[219] Yao H, Sun L, Li J, Zhou X, Li R, Shao R, et al. A novel therapeutic siRNA nanoparticle designed for dual-targeting CD44 and Gli1 of gastric cancer stem cells. Int J Nanomed 2020; 15:7013-34.

[220] Lubanska D, Alrashed S, Mason GT, Nadeem F, Awada A, DiPasquale M, et al. Impairing proliferation of glioblastoma multiforme with CD44+selective conjugated polymer nanoparticles. Sci Rep 2022; 12(1):12078.

[221] Das SK, Roy S, Das A, Chowdhury A, Chatterjee N, Bhaumik A. A conjugated 2D covalent organic framework as a drug delivery vehicle towards triple negative breast cancer malignancy. Nanoscale Adv 2022; 4(10):2313-20.

[222] Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007; 7(11):834-46.

[223] Jahanban-Esfahlan R, Seidi K, Manjili MH, Jahanban-Esfahlan A, Javaheri T, Zare P. Tumor cell dormancy: threat or opportunity in the fight against cancer. Cancers 2019; 11(8):1207.

[224] Santos-de-Frutos K, Djouder N. When dormancy fuels tumour relapse. Commun Biol 2021; 4(1):747.

[225] Nahas GR, Sherman LS, Sinha G, El Far MH, Petryna A, Munoz SM, et al.Increased expression of musashi 1 on breast cancer cells has implication to understand dormancy and survival in bone marrow. Aging (Albany NY) 2023; 15(9):3230-48.

[226] Talukdar S, Bhoopathi P, Emdad L, Das S, Sarkar D, Fisher PB. Dormancy and cancer stem cells: an enigma for cancer therapeutic targeting. Adv Cancer Res 2019; 141:43-84.

[227] Ayoubi-Joshaghani MH, Seidi K, Azizi M, Jaymand M, Javaheri T, Jahanban-Esfahlan R, et al. Potential applications of advanced nano/hydrogels in biomedicine: static, dynamic, multi-stage, and bioinspired. Adv Fun Mater 2020; 30(45):2004098.