Next-generation strategies against prostate cancer: natural products and nanomedicine targeting prostate cancer stem cells

Recurrence, metastasis, and treatment resistance are significant issues in prostate cancer management. Evidence increasingly substantiates the notion that prostate cancer stem cells (PCSCs) initiate cancer, facilitate its progression, and complicate therapy. Thus, targeting PCSCs may provide a feasible strategy for addressing incurable or recurrent illnesses. Research indicates that natural compounds derived from medicinal plants and foods may combat cancer, particularly by targeting cancer stem cells via modulation of signals from the Wnt/β-catenin, Notch, Hedgehog, and Phosphoinositide 3-kinase (PI3K)/Protein kinase B (AKT)/Mechanistic target of rapamycin (mTOR) signaling pathway. Nonetheless, the majority of these bioactive chemicals exhibit low solubility in water, inadequately penetrate the circulation, and are rapidly eliminated by the body before they can be effectively used in medical applications. Nanotechnology has enhanced the delivery, production, and targeting of certain natural products. Phytochemicals may be effectively administered to PCSCs inside tumours using liposomes, polymeric nanoparticles, dendrimers, micelles, and exosomes. Moreover, stimuli-responsive nanoplatforms may be constructed to concurrently administer several pharmaceuticals. This review analyses the function of PCSCs in prostate cancer, identifies key natural chemicals that target PCSCs, and evaluates the potential of nanotechnology to amplify the efficacy of these natural products. Furthermore, we examine current obstacles, unresolved enquiries, and anticipated trajectories for the implementation of natural nanomedicine therapies in PCSCs.

Prostate cancer stem cells; Natural products; Nanomedicine; Phytochemicals; Drug delivery; Cancer recurrence; Tumor resistance; Precision oncology

[1] Adekiya TA, Owoseni O. Emerging frontiers in nanomedicine targeted therapy for prostate cancer. Cancer Treatment and Research Communications. 2023; 37: 100778.

[2] Andrew J, Ezra-Manicum AL, Witika BA. Developments in radionanotheranostic strategies for precision diagnosis and treatment of prostate cancer. EJNMMI Radiopharmacy and Chemistry. 2024; 9: 62.

[3] Semwal P, Painuli S, Abu-Izneid T, Rauf A, Sharma A, Daştan SD, et al. Diosgenin: an updated pharmacological review and therapeutic perspectives. Oxidative Medicine and Cellular Longevity. 2022; 2022: 1035441.

[4] Schafer EJ, Laversanne M, Sung H, Soerjomataram I, Briganti A, Dahut W, et al. Recent patterns and trends in global prostate cancer incidence and mortality: an update. European Urology. 2025; 87: 302–313.

[5] Acquah J, Bosson-Amedenu S, Eyiah-Bediako F, Buabeng A, Ouerfelli N. Modelling incidence and mortality cancer parameters with respect to GLOBOCAN 2020age standardized world estimates. Heliyon. 2024; 10: e36836.

[6] Giona S. The epidemiology of prostate cancer. 2021. Available at: https://doi.org/10.36255/exonpublications.prostatecancer.epidemiology.2021 (Accessed: 07 June 2025).

[7] Choi E, Buie J, Camacho J, Sharma P, de Riese WTW. Evolution of androgen deprivation therapy (ADT) and its new emerging modalities in prostate cancer: an update for practicing urologists, clinicians and medical providers. Research and Reports in Urology. 2022; 14: 87–108.

[8] He MX, Cuoco MS, Crowdis J, Bosma-Moody A, Zhang Z, Bi K, et al. Transcriptional mediators of treatment resistance in lethal prostate cancer. Nature Medicine. 2021; 27: 426–433.

[9] Liang H, Zhou B, Li P, Zhang X, Zhang S, Zhang Y, et al. Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy. Annals of Medicine. 2025; 57: 2442067.

[10] Liu S, Zhang X, Wang W, Li X, Sun X, Zhao Y, et al. Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer. Molecular Cancer. 2024; 23: 261.

[11] Lindell E, Zhong L, Zhang X. Quiescent cancer cells—a potential therapeutic target to overcome tumor resistance and relapse. International Journal of Molecular Sciences. 2023; 24: 3762.

[12] Zhu B, Qu S. The relationship between diabetes mellitus and cancers and its underlying mechanisms. Frontiers in Endocrinology. 2022; 13: 800995.

[13] Wang Z, Dai Z, Gao Y, Zhao Z, Li Z, Wang L, et al. Development of a machine learning-based predictive risk model combining fatty acid metabolism and ferroptosis for immunotherapy response and prognosis in prostate cancer. Discover Oncology. 2025; 16: 744.

[14] Jenča A, Mills DK, Ghasemi H, Saberian E, Jenča A, Karimi Forood AM, et al. Herbal therapies for cancer treatment: a review of phytotherapeutic efficacy. Biologics. 2024; 18: 229–255.

[15] Tuli HS, Garg VK, Bhushan S, Uttam V, Sharma U, Jain A, et al. Natural flavonoids exhibit potent anticancer activity by targeting microRNAs in cancer: a signature step hinting towards clinical perfection. Translational Oncology. 2023; 27: 101596.

[16] Alnasser SM, Alrobian AS, Alfayez MS, Almutairi OT, Almutairi SS, Alkeraidees TS. Pharmacological modulation of stem cells signaling pathway for therapeutic applications. Stem Cell Research & Therapy. 2025; 16: 327.

[17] Ali Abdalla YO, Subramaniam B, Nyamathulla S, Shamsuddin N, Arshad NM, Mun KS, et al. Natural products for cancer therapy: a review of their mechanism of actions and toxicity in the past decade. Journal of Tropical Medicine. 2022; 2022: 5794350.

[18] El-Saadony MT, Yang T, Korma SA, Sitohy M, Abd El-Mageed TA, Selim S, et al. Impacts of turmeric and its principal bioactive curcumin on human health: pharmaceutical, medicinal, and food applications: a comprehensive review. Frontiers in Nutrition. 2023; 9: 1040259.

[19] Bhange M, Telange D. Convergence of nanotechnology and artificial intelligence in the fight against liver cancer: a comprehensive review. Discover Oncology. 2025; 16: 77.

[20] Uti DE, Atangwho IJ, Alum EU, Ntaobeten E, Obeten UN, Bawa I, et al. Antioxidants in cancer therapy mitigating lipid peroxidation without compromising treatment through nanotechnology. Discover Nano. 2025; 20: 70.

[21] Martín-Contreras M, Navarro-Marchal SA, Peula-García JM, Jódar-Reyes AB. Progress and hurdles of therapeutic nanosystems against cancer. Pharmaceutics. 2022; 14: 388.

[22] Salehi S, Naghib SM, Garshasbi HR, Ghorbanzadeh S, Zhang W. Smart stimuli-responsive injectable gels and hydrogels for drug delivery and tissue engineering applications: a review. Frontiers in Bioengineering and Biotechnology. 2023; 11: 1104126.

[23] Maleki H, Aiyelabegan HT, Javadi P, Abdi F, Mirzavi F, Zarei Behjani Z, et al. Nanotechnology-mediated precision drug delivery strategies for breast cancer treatment. Biomedicine & Pharmacotherapy. 2025; 188: 118224.

[24] Rossi F, Noren H, Jove R, Beljanski V, Grinnemo KH. Differences and similarities between cancer and somatic stem cells: therapeutic implications. Stem Cell Research & Therapy. 2020; 11: 489.

[25] Ionescu F, Zhang J. How we treat metastatic castration-sensitive prostate cancer. Cancer Control. 2024; 31: 10732748241274190.

[26] Varaprasad GL, Gupta VK, Prasad K, Kim E, Tej MB, Mohanty P, et al. Recent advances and future perspectives in the therapeutics of prostate cancer. Experimental Hematology & Oncology. 2023; 12: 80.

[27] Obisi JN, Abimbola ANJ, Babaleye OA, Atidoglo PK, Usin SG, Nwanaforo EO, et al. Unveiling the future of cancer stem cell therapy: a narrative exploration of emerging innovations. Discover Oncology. 2025; 16: 373.

[28] Zhang P, Zhang C, Li J, Han J, Liu X, Yang H. The physical microenvironment of hematopoietic stem cells and its emerging roles in engineering applications. Stem Cell Research & Therapy. 2019; 10: 327.

[29] Lee SA, Cho GJ, Kim D, Kim DH. Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis. Frontiers in Cell and Developmental Biology. 2024; 12: 1335636.

[30] Du G, Huang X, Su P, Yang Y, Chen S, Huang T, et al. The role of SOX transcription factors in prostate cancer: focusing on SOX2. Genes & Diseases. 2025; 12: 101692.

[31] Yehya A, Youssef J, Hachem S, Ismael J, Abou-Kheir W. Tissue-specific cancer stem/progenitor cells: therapeutic implications. World Journal of Stem Cells. 2023; 15: 323–341.

[32] Borsdorf S, Zeug A, Wu Y, Mitroshina E, Vedunova M, Gaitonde SA, et al. The cell adhesion molecule CD44 acts as a modulator of 5-HT7 receptor functions. Cell Communication and Signaling. 2024; 22: 563.

[33] Valentini V, Santi R, Silvestri V, Saieva C, Roviello G, Amorosi A, et al. CD44 methylation levels in androgen-deprived prostate cancer: a putative epigenetic modulator of tumor progression. International Journal of Molecular Sciences. 2025; 26: 2516.

[34] Pleskač P, Fargeas CA, Veselska R, Corbeil D, Skoda J. Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease. Cellular & Molecular Biology Letters. 2024; 29: 41.

[35] Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Experimental Hematology & Oncology. 2020; 9: 36.

[36] Li S, Sampson C, Liu C, Piao HL, Liu HX. Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities. Cell Communication and Signaling. 2023; 21: 266.

[37] Gires O, Pan M, Schinke H, Canis M, Baeuerle PA. Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years? Cancer and Metastasis Reviews. 2020; 39: 969–987.

[38] Mei W, Lin X, Kapoor A, Gu Y, Zhao K, Tang D. The contributions of prostate cancer stem cells in prostate cancer initiation and metastasis. Cancers. 2019; 11: 434.

[39] Han S, Chen X, Li Z. Innate immune program in formation of tumor-initiating cells from cells-of-origin of breast, prostate, and ovarian cancers. Cancers. 2023; 15: 757.

[40] Liu M, Yang J, Xu B, Zhang X. Tumor metastasis: mechanistic insights and therapeutic interventions. MedComm. 2021; 2: 587–617.

[41] Leggett SE, Hruska AM, Guo M, Wong IY. The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems. Cell Communication and Signaling. 2021; 19: 32.

[42] Akhmetkaliyev A, Alibrahim N, Shafiee D, Tulchinsky E. EMT/MET plasticity in cancer and Go-or-Grow decisions in quiescence: the two sides of the same coin? Molecular Cancer. 2023; 22: 90.

[43] Zhong H, Zhou S, Yin S, Qiu Y, Liu B, Yu H. Tumor microenvironment as niche constructed by cancer stem cells: breaking the ecosystem to combat cancer. Journal of Advanced Research. 2025; 71: 279–296.

[44] Zhang S, Zhang T, Kinsella GK, Curtin JF. A review of the efficacy of prostate cancer therapies against castration-resistant prostate cancer. Drug Discovery Today. 2025; 30: 104384.

[45] Wahab A, Siddique H R. An update understanding of stemness and chemoresistance of prostate cancer. Expert Review of Anticancer Therapy. 2025; 25: 215–228.

[46] Cai M, Song XL, Li XA, Chen M, Guo J, Yang DH, et al. Current therapy and drug resistance in metastatic castration-resistant prostate cancer. Drug Resistance Updates. 2023; 68: 100962.

[47] Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. Journal of Hematology & Oncology. 2020; 13: 165.

[48] Shah K, Kazi JU. Phosphorylation-dependent regulation of Wnt/beta-catenin signaling. Frontiers in Oncology. 2022; 12: 858782.

[49] Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, et al. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. Journal of Hematology & Oncology. 2024; 17: 46.

[50] Orzechowska M, Anusewicz D, Bednarek AK. Functional gene expression differentiation of the notch signaling pathway in female reproductive tract tissues—a comprehensive review with analysis. Frontiers in Cell and Developmental Biology. 2020; 8: 592616.

[51] Akil A, Gutiérrez-García AK, Guenter R, Rose JB, Beck AW, Chen H, et al. Notch signaling in vascular endothelial cells, angiogenesis, and tumor progression: an update and prospective. Frontiers in Cell and Developmental Biology. 2021; 9: 642352.

[52] Carballo GB, Honorato JR, de Lopes GPF, Spohr TCLSE. A highlight on sonic hedgehog pathway. Cell Communication and Signaling. 2018; 16: 11.

[53] Jing J, Wu Z, Wang J, Luo G, Lin H, Fan Y, et al. Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies. Signal Transduction and Targeted Therapy. 2023; 8: 315.

[54] Goncharov AP, Dicusari Elissaiou C, Ben Aharon Farzalla E, Akhvlediani G, Vashakidze N, Kharaishvili G. Signalling pathways in a nutshell: from pathogenesis to therapeutical implications in prostate cancer. Annals of Medicine. 2025; 57: 2474175.

[55] Hashimoto S, Hashimoto A, Muromoto R, Kitai Y, Oritani K, Matsuda T. Central roles of STAT3-mediated signals in onset and development of cancers: tumorigenesis and immunosurveillance. Cells. 2022; 11: 2618.

[56] Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm. 2022; 3: e176.

[57] Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduction and Targeted Therapy. 2025; 10: 106.

[58] Sher G, Masoodi T, Patil K, Akhtar S, Kuttikrishnan S, Ahmad A, et al. Dysregulated FOXM1 signaling in the regulation of cancer stem cells. Seminars in Cancer Biology. 2022; 86: 107–121.

[59] Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling. International Journal of Molecular Sciences. 2020; 21: 4507.

[60] Esfini Farahani M, Zhang Y, Akinyemi AO, Seilani F, Alam MR, Liu X. Unlocking the role of OCT4 in cancer lineage plasticity: a cross-cancer perspective with an emphasis on prostate cancer. Biomedicines. 2025; 13: 1642.

[61] Wu X, Xu Y, Liang Q, Yang X, Huang J, Wang J, et al. Recent advances in dual PI3K/mTOR inhibitors for tumour treatment. Frontiers in Pharmacology. 2022; 13: 875372.

[62] Huang B, Lang X, Li X. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Frontiers in Oncology. 2022; 12: 1023177.

[63] Veilleux C, Roy MÈ, Zgheib A, Desjarlais M, Annabi B. Evidence for a JAK2/STAT3 proinflammatory and vasculogenic mimicry interrelated molecular signature in adipocyte-derived mesenchymal stromal/stem cells. Cell Communication and Signaling. 2025; 23: 291.

[64] Zhang S, Xiong X, Sun Y. Functional characterization of SOX2 as an anticancer target. Signal Transduction and Targeted Therapy. 2020; 5: 135.

[65] DiNatale A, Castelli MS, Nash B, Meucci O, Fatatis A. Regulation of tumor and metastasis initiation by chemokine receptors. Journal of Cancer. 2022; 13: 3160–3176.

[66] Talukdar S, Das SK, Pradhan AK, Emdad L, Windle JJ, Sarkar D, et al. MDA-9/Syntenin (SDCBP) is a critical regulator of chemoresistance, survival and stemness in prostate cancer stem cells. Cancers. 2019; 12: 53.

[67] Cao Y, Yi Y, Han C, Shi B. NF-κB signaling pathway in tumor microenvironment. Frontiers in Immunology. 2024; 15: 1476030.

[68] Krajka-Kuźniak V, Belka M, Papierska K. Targeting STAT3 and NF-κB signaling pathways in cancer prevention and treatment: the role of chalcones. Cancers. 2024; 16: 1092.

[69] Chaves LP, Melo CM, Saggioro FP, Reis RBD, Squire JA. Epithelial-mesenchymal transition signaling and prostate cancer stem cells: emerging biomarkers and opportunities for precision therapeutics. Genes. 2021; 12: 1900.

[70] Sheikh KA, Amjad M, Irfan MT, Anjum S, Majeed T, Riaz MU, et al. Exploring TGF-β signaling in cancer progression: prospects and therapeutic strategies. OncoTargets and Therapy. 2025; 18: 233–262.

[71] Deng F, Wu Z, Zou F, Wang S, Wang X. The Hippo-YAP/TAZ signaling pathway in intestinal self-renewal and regeneration after injury. Frontiers in Cell and Developmental Biology. 2022; 10: 894737.

[72] Zhang Q, Han X, Chen J, Xie X, Xu J, Zhao Y, et al. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell density-dependent proinflammatory responses. Journal of Biological Chemistry. 2018; 293: 18071–18085.

[73] Li X, Zhuo S, Cho YS, Liu Y, Yang Y, Zhu J, et al. YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth. The EMBO Journal. 2023; 42: e112184.

[74] Tresas T, Isaioglou I, Roussis A, Haralampidis K. A brief overview of the epigenetic regulatory mechanisms in plants. International Journal of Molecular Sciences. 2025; 26: 4700.

[75] Bae W, Ra EA, Lee MH. Epigenetic regulation of reprogramming and pluripotency: insights from histone modifications and their implications for cancer stem cell therapies. Frontiers in Cell and Developmental Biology. 2025; 13: 1559183.

[76] Singh A, Malvankar S, Ravi Kumar YS, Seervi M, Srivastava RK, Verma B. Role of various non-coding RNAs in EMT, cancer, and metastasis: recent trends and future perspective. Advances in Cancer Biology-Metastasis. 2022; 4: 100039.

[77] Alum EU, Nwuruku OA, Ugwu OPC, Uti DE, Alum BN, Edwin N. Harnessing nature: plant-derived nanocarriers for targeted drug delivery in cancer therapy. Phytomedicine Plus. 2025; 5: 100828.

[78] Wahnou H, El Kebbaj R, Liagre B, Sol V, Limami Y, Duval RE. Curcumin-based nanoparticles: advancements and challenges in tumor therapy. Pharmaceutics. 2025; 17: 114.

[79] Oršolić N, Jazvinšćak Jembrek M. Molecular and cellular mechanisms of propolis and its polyphenolic compounds against cancer. International Journal of Molecular Sciences. 2022; 23: 10479.

[80] Capasso L, De Masi L, Sirignano C, Maresca V, Basile A, Nebbioso A, et al. Epigallocatechin gallate (EGCG): pharmacological properties, biological activities and therapeutic potential. Molecules. 2025; 30: 654.

[81] Coutinho LL, Junior TCT, Rangel MC. Sulforaphane: an emergent anti-cancer stem cell agent. Frontiers in Oncology. 2023; 13: 1089115.

[82] Pejčić T, Zeković M, Bumbaširević U, Kalaba M, Vovk I, Bensa M, et al. The role of isoflavones in the prevention of breast cancer and prostate cancer. Antioxidants. 2023; 12: 368.

[83] Roy RV, Suman S, Das TP, Luevano JE, Damodaran C. Withaferin A, a steroidal lactone from Withania somnifera, induces mitotic catastrophe and growth arrest in prostate cancer cells. Journal of Natural Products. 2013; 76: 1909–1915.

[84] Murakami T, Bodor E, Bodor N. Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: part 2. development of oral dosage formulations. Expert Opinion on Drug Metabolism & Toxicology. 2023; 19: 139–148.

[85] Azizi E, Fouladdel S, Komeili Movahhed T, Modaresi F, Barzegar E, Ghahremani MH, et al. Quercetin effects on cell cycle arrest and apoptosis and doxorubicin activity in T47D cancer stem cells. Asian Pacific Journal of Cancer Prevention. 2022; 23: 4145–4154.

[86] Hsu CY, Rajabi S, Hamzeloo-Moghadam M, Kumar A, Maresca M, Ghildiyal P. Sesquiterpene lactones as emerging biomolecules to cease cancer by targeting apoptosis. Frontiers in Pharmacology. 2024; 15: 1371002.

[87] Cao H, Feng Y, Sun P, Chen L, Wang D, Gao R. Zhoushi Qiling decoction inhibits proliferation of human prostate cancer cells through IL6/STAT3 pathway. Journal of Cancer. 2023; 14: 2246–2254.

[88] Sferrazza G, Corti M, Brusotti G, Pierimarchi P, Temporini C, Serafino A, et al. Nature-derived compounds modulating Wnt/β-catenin pathway: a preventive and therapeutic opportunity in neoplastic diseases. Acta Pharmaceutica Sinica B. 2020; 10: 1814–1834.

[89] Okpoghono J, Isoje EF, Igbuku UA, Ekayoda O, Omoike GO, Adonor TO, et al. Natural polyphenols: a protective approach to reduce colorectal cancer. Heliyon. 2024; 10: e32390.

[90] Zhou C, Huang Y, Nie S, Zhou S, Gao X, Chen G. Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent. European Journal of Medical Research. 2023; 28: 297.

[91] Cai J, Hu Q, He Z, Chen X, Wang J, Yin X, et al. Scutellaria baicalensis Georgi and their natural flavonoid compounds in the treatment of ovarian cancer: a review. Molecules. 2023; 28: 5082.

[92] Pal RR, Rajpal V, Singh P, Saraf SA. Recent findings on thymoquinone and its applications as a nanocarrier for the treatment of cancer and rheumatoid arthritis. Pharmaceutics. 2021; 13: 775.

[93] Kashif M, Hwang Y, Kim WJ, Kim G. In-vitro morphological assessment of apoptosis induced by nimbolide; a limonoid from Azadirachta indica (neem tree). Iranian Journal of Pharmaceutical Research. 2019; 18: 846–859.

[94] Kopytko P, Piotrowska K, Janisiak J, Tarnowski M. Garcinol—a natural histone acetyltransferase inhibitor and new anti-cancer epigenetic drug. International Journal of Molecular Sciences. 2021; 22: 2828.

[95] Tak Y, Kaur M, Chitranashi A, Samota MK, Verma P, Bali M, et al. Fenugreek derived diosgenin as an emerging source for diabetic therapy. Frontiers in Nutrition. 2024; 11: 1280100.

[96] Ghosh R, Samanta P, Sarkar R, Biswas S, Saha P, Hajra S, et al. Targeting HIF-1α by natural and synthetic compounds: a promising approach for anti-cancer therapeutics development. Molecules. 2022; 27: 5192.

[97] Uti DE, Alum EU, Atangwho IJ, Ugwu OP, Egbung GE, Aja PM. Lipid-based nano-carriers for the delivery of anti-obesity natural compounds: advances in targeted delivery and precision therapeutics. Journal of Nanobiotechnology. 2025; 23: 336.

[98] Liu Y, Liang Y, Yuhong J, Xin P, Han JL, Du Y, et al. Advances in nanotechnology for enhancing the solubility and bioavailability of poorly soluble drugs. Drug Design, Development and Therapy. 2024; 18: 1469–1495.

[99] Alghamdi MA, Fallica AN, Virzì N, Kesharwani P, Pittalà V, Greish K. The promise of nanotechnology in personalized medicine. Journal of Personalized Medicine. 2022; 12: 673.

[100] Anwar DM, Hedeya HY, Ghozlan SH, Ewas BM, Khattab SN. Surface-modified lipid-based nanocarriers as a pivotal delivery approach for cancer therapy: application and recent advances in targeted cancer treatment‏. Beni-Suef University Journal of Basic and Applied Sciences. 2024; 13: 106.

[101] Teixeira MI, Lopes CM, Amaral MH, Costa PC. Surface-modified lipid nanocarriers for crossing the blood-brain barrier (BBB): a current overview of active targeting in brain diseases. Colloids and Surfaces B: Biointerfaces. 2023; 221: 112999.

[102] Taher M, Susanti D, Haris MS, Rushdan AA, Widodo RT, Syukri Y, et al. PEGylated liposomes enhance the effect of cytotoxic drug: a review. Heliyon. 2023; 9: e13823.

[103] Nair A, Chandrashekhar H R, Day CM, Garg S, Nayak Y, Shenoy PA, et al. Polymeric functionalization of mesoporous silica nanoparticles: biomedical insights. International Journal of Pharmaceutics. 2024; 660: 124314.

[104] Wang W, Zhou M, Xu Y, Peng W, Zhang S, Li R, et al. Resveratrol-loaded TPGS-resveratrol-solid lipid nanoparticles for multidrug-resistant therapy of breast cancer: in vivo and in vitro study. Frontiers in Bioengineering and Biotechnology. 2021; 9: 762489.

[105] Pérez-Ferreiro M, M Abelairas A, Criado A, Gómez IJ, Mosquera J. Dendrimers: exploring their wide structural variety and applications. Polymers. 2023; 15: 4369.

[106] Abedi-Gaballu F, Dehghan G, Ghaffari M, Yekta R, Abbaspour-Ravasjani S, Baradaran B, et al. PAMAM dendrimers as efficient drug and gene delivery nanosystems for cancer therapy. Applied Materials Today. 2018; 12: 177–190.

[107] Araujo-Abad S, Berna JM, Lloret-Lopez E, López-Cortés A, Saceda M, de Juan Romero C. Exosomes: from basic research to clinical diagnostic and therapeutic applications in cancer. Cellular Oncology. 2025; 48: 269–293.

[108] Mukerjee N, Alharbi HM, Maitra S, Anand K, Thorat N, Gorai S. Exosomes in liquid biopsy and oncology: nanotechnological interplay and the quest to overcome cancer drug resistance. The Journal of Liquid Biopsy. 2023; 3: 100134.

[109] Lu J, Zhang Y, Yang X, Zhao H. Harnessing exosomes as cutting-edge drug delivery systems for revolutionary osteoarthritis therapy. Biomedicine & Pharmacotherapy. 2023; 165: 115135.

[110] Rugină D, Socaciu MA, Nistor M, Diaconeasa Z, Cenariu M, Tabaran FA, et al. Liposomal and nanostructured lipid nanoformulations of a pentacyclic triterpenoid birch bark extract: structural characterization and in vitro effects on melanoma B16-F10 and Walker 256 tumor cells apoptosis. Pharmaceuticals. 2024; 17: 1630.

[111] Kevadiya BD, Woldstad C, Ottemann BM, Dash P, Sajja BR, Lamberty B, et al. Multimodal theranostic nanoformulations permit magnetic resonance bioimaging of antiretroviral drug particle tissue-cell biodistribution. Theranostics. 2018; 8: 256–276.

[112] Yan Y, Kulsoom, Sun Y, Li Y, Wang Z, Xue L, et al. Advancing cancer therapy: nanomaterial-based encapsulation strategies for enhanced delivery and efficacy of curcumin. Materials Today Bio. 2025; 33: 101963.

[113] Cavalcante de Freitas PG, Rodrigues Arruda B, Araújo Mendes MG, Barroso de Freitas JV, da Silva ME, Sampaio TL, et al. Resveratrol-loaded polymeric nanoparticles: the effects of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on physicochemical and biological properties against breast cancer in vitro and in vivo. Cancers. 2023; 15: 2802.

[114] Tomar R, Das SS, Balaga VKR, Tambe S, Sahoo J, Rath SK, et al. Therapeutic implications of dietary polyphenols-loaded nanoemulsions in cancer therapy. ACS Applied Bio Materials. 2024; 7: 2036–2053.

[115] Nikolova MP, Kumar EM, Chavali MS. Updates on responsive drug delivery based on liposome vehicles for cancer treatment. Pharmaceutics. 2022; 14: 2195.

[116] Peter S, Khwaza V, Alven S, Naki T, Aderibigbe BA. PEGylated nanoliposomes encapsulated with anticancer drugs for breast and prostate cancer therapy: an update. Pharmaceutics. 2025; 17: 190.

[117] El-Hammadi MM, Arias JL. Recent advances in the surface functionalization of PLGA-based nanomedicines. Nanomaterials. 2022; 12: 354.

[118] Omidian H, Wilson RL. PLGA implants for controlled drug delivery and regenerative medicine: advances, challenges, and clinical potential. Pharmaceuticals. 2025; 18: 631.

[119] Pandey S, Shaikh F, Gupta A, Tripathi P, Yadav JS. A recent update: solid lipid nanoparticles for effective drug delivery. Advanced Pharmaceutical Bulletin. 2022; 12: 17–33.

[120] Borges A, Freitas V, Mateus N, Fernandes I, Oliveira J. Solid lipid nanoparticles as carriers of natural phenolic compounds. Antioxidants. 2020; 9: 998.

[121] Alamos-Musre S, Beltrán-Chacana D, Moyano J, Márquez-Miranda V, Duarte Y, Miranda-Rojas S, et al. From structure to function: the promise of PAMAM dendrimers in biomedical applications. Pharmaceutics. 2025; 17: 927.

[122] Guzmán Rodríguez A, Sablón Carrazana M, Rodríguez Tanty C, Malessy MJA, Fuentes G, Cruz LJ. Smart polymeric micelles for anticancer hydrophobic drugs. Cancers. 2022; 15: 4.

[123] Wang Q, Atluri K, Tiwari AK, Babu RJ. Exploring the application of micellar drug delivery systems in cancer nanomedicine. Pharmaceuticals. 2023; 16: 433.

[124] Quesada-Vázquez S, Eseberri I, Les F, Pérez-Matute P, Herranz-López M, Atgié C, et al. Polyphenols and metabolism: from present knowledge to future challenges. Journal of Physiology and Biochemistry. 2024; 80: 603–625.

[125] Alimohammadvand S, Kaveh Zenjanab M, Mashinchian M, Shayegh J, Jahanban-Esfahlan R. Recent advances in biomimetic cell membrane-camouflaged nanoparticles for cancer therapy. Biomedicine & Pharmacotherapy. 2024; 177: 116951.

[126] Frickenstein AN, Hagood JM, Britten CN, Abbott BS, McNally MW, Vopat CA, et al. Mesoporous silica nanoparticles: properties and strategies for enhancing clinical effect. Pharmaceutics. 2021; 13: 570.

[127] Dutta Gupta Y, Mackeyev Y, Krishnan S, Bhandary S. Mesoporous silica nanotechnology: promising advances in augmenting cancer theranostics. Cancer Nanotechnology. 2024; 15: 9.

[128] Gajbhiye KR, Salve R, Narwade M, Sheikh A, Kesharwani P, Gajbhiye V. Lipid polymer hybrid nanoparticles: a custom-tailored next-generation approach for cancer therapeutics. Molecular Cancer. 2023; 22: 160.

[129] Mohanty A, Uthaman S, Park IK. Utilization of polymer-lipid hybrid nanoparticles for targeted anti-cancer therapy. Molecules. 2020; 25: 4377.

[130] Chandrasekharan P, Tay ZW, Hensley D, Zhou XY, Fung BK, Colson C, et al. Using magnetic particle imaging systems to localize and guide magnetic hyperthermia treatment: tracers, hardware, and future medical applications. Theranostics. 2020; 10: 2965–2981.

[131] Radeva L, Yoncheva K. Nanogels-innovative drug carriers for overcoming biological membranes. Gels. 2025; 11: 124.

[132] Nocito MC, De Luca A, Prestia F, Avena P, La Padula D, Zavaglia L, et al. Antitumoral activities of curcumin and recent advances to improve its oral bioavailability. Biomedicines. 2021; 9: 1476.

[133] Wu J, Ji H, Li T, Guo H, Xu H, Zhu J, et al. Targeting the prostate tumor microenvironment by plant-derived natural products. Cellular Signalling. 2024; 115: 111011.

[134] Xiong RG, Huang SY, Wu SX, Zhou DD, Yang ZJ, Saimaiti A, et al. Anticancer effects and mechanisms of berberine from medicinal herbs: an update review. Molecules. 2022; 27: 4523.

[135] Jin X, Yang Q, Cai N, Zhang Z. A cocktail of betulinic acid, parthenolide, honokiol and ginsenoside Rh2 in liposome systems for lung cancer treatment. Nanomedicine. 2020; 15: 41–54.

[136] Nadile M, Kornel A, Sze NSK, Tsiani E. A comprehensive review of genistein’s effects in preclinical models of cervical cancer. Cancers. 2023; 16: 35.

[137] Greco G, Agafonova A, Cosentino A, Cardullo N, Muccilli V, Puglia C, et al. Solid lipid nanoparticles encapsulating a benzoxanthene derivative in a model of the human blood-brain barrier: modulation of angiogenic parameters and inflammation in vascular endothelial growth factor-stimulated angiogenesis. Molecules. 2024; 29: 3103.

[138] Peanlikhit T, Aryal U, Welsh JS, Shroyer KR, Rithidech KN. Evaluation of the inhibitory potential of apigenin and related flavonoids on various proteins associated with human diseases using AutoDock. International Journal of Molecular Sciences. 2025; 26: 2548.

[139] Homayoonfal M, Asemi Z, Yousefi B. Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis. Cellular & Molecular Biology Letters. 2022; 27: 21.

[140] Almatroodi SA, Almatroudi A, Alharbi HOA, Khan AA, Rahmani AH. Effects and mechanisms of luteolin, a plant-based flavonoid, in the prevention of cancers via modulation of inflammation and cell signaling molecules. Molecules. 2024; 29: 1093.

[141] Iqbal Y, Asghar S, Hanif R, Amin F. PMA-coated gold nanoparticles functionalized with diamine-PEG conjugated with betulinic acid for in vitro mitochondrial-targeted anticancer and ROS detection study against MDA-MB-231 cell lines. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2025; 721: 137170.

[142] Aslam R, Tiwari V, Upadhyay P, Tiwari A. Revolutionizing therapeutic delivery: diosgenin-loaded solid lipid nanoparticles unleash advanced carriers. International Journal of Applied Pharmaceutics. 2024; 16: 124–133.

[143] Bakry SM, El-Shiekh RA, Hatem S, Mandour AA, El-Dessouki AM, Bishr A, et al. Therapeutic applications of ursolic acid: a comprehensive review and utilization of predictive tools. Future Journal of Pharmaceutical Sciences. 2025; 11: 48.

[144] Morshed AKMH, Paul S, Hossain A, Basak T, Hossain MS, Hasan MM, et al. Baicalein as promising anticancer agent: a comprehensive analysis on molecular mechanisms and therapeutic perspectives. Cancers. 2023; 15: 2128.

[145] Kumar S, Mathew SO, Aharwal RP, Tulli HS, Mohan CD, Sethi G, et al. Withaferin A: a pleiotropic anticancer agent from the Indian medicinal plant withania somnifera (L.) Dunal. Pharmaceuticals. 2023; 16: 160.

[146] Zhu Y, Wang A, Zhang S, Kim J, Xia J, Zhang F, et al. Paclitaxel-loaded ginsenoside Rg3 liposomes for drug-resistant cancer therapy by dual targeting of the tumor microenvironment and cancer cells. Journal of Advanced Research. 2023; 49: 159–173.

[147] Ghasemi M, Nowroozzadeh MH, Ghorat F, Iraji A, Hashempur MH. Piperine and its nanoformulations: a mechanistic review of their anti-cancer activities. Biomedicine & Pharmacotherapy. 2025; 187: 118075.

[148] Yakubu J, Natsaridis E, du Toit T, Barata IS, Tagit O, Pandey AV. Nanoparticles with curcumin and piperine modulate steroid biosynthesis in prostate cancer. Scientific Reports. 2025; 15: 13613.

[149] Basheer I, Wang H, Li G, Jehan S, Raza A, Du C, et al. β-caryophyllene sensitizes hepatocellular carcinoma cells to chemotherapeutics and inhibits cell malignancy through targeting MAPK signaling pathway. Frontiers in Pharmacology. 2024; 15: 1492670.

[150] Fahmy SA, Elghanam R, Rashid G, Youness RA, Sedky NK. Emerging tendencies for the nano-delivery of gambogic acid: a promising approach in oncotherapy. RSC Advances. 2024; 14: 4666–4691.

[151] Gogola S, Rejzer M, Bahmad HF, Alloush F, Omarzai Y, Poppiti R. Anti-cancer stem-cell-targeted therapies in prostate cancer. Cancers. 2023; 15: 1621.

[152] Trofin AM, Scripcariu DV, Filipiuc SI, Neagu AN, Filipiuc LE, Tamba BI, et al. From nature to nanomedicine: enhancing the antitumor efficacy of rhein, curcumin, and resveratrol. Medicina. 2025; 61: 981.

[153] Teixeira PV, Fernandes E, Soares TB, Adega F, Lopes CM, Lúcio M. Natural compounds: co-delivery strategies with chemotherapeutic agents or nucleic acids using lipid-based nanocarriers. Pharmaceutics. 2023; 15: 1317.

[154] Majumder J, Minko T. Multifunctional and stimuli-responsive nanocarriers for targeted therapeutic delivery. Expert Opinion on Drug Delivery. 2021; 18: 205–227.

[155] Zhou Y, Wang X, Tian X, Zhang D, Cui H, Du W, et al. Stealth missiles with precision guidance: a novel multifunctional nano-drug delivery system based on biomimetic cell membrane coating technology. Materials Today Bio. 2025; 33: 101922.

[156] Aghajanzadeh M, Zamani M, Rajabi Kouchi F, Eixenberger J, Shirini D, Estrada D, et al. Synergic antitumor effect of photodynamic therapy and chemotherapy mediated by nano drug delivery systems. Pharmaceutics. 2022; 14: 322.

[157] Fu Z, Xiang J. Aptamer-functionalized nanoparticles in targeted delivery and cancer therapy. International Journal of Molecular Sciences. 2020; 21: 9123.

[158] Nsairat H, Khater D, Odeh F, Al-Adaileh F, Al-Taher S, Jaber AM, et al. Lipid nanostructures for targeting brain cancer. Heliyon. 2021; 7: e07994.

[159] Xia B, Zhu Q. Aptamer-ODN chimeras: enabling cell-specific ODN targeting therapy. Cells. 2025; 14: 697.

[160] Ragab EM, Gamal DME, El-Najjar FF, Elkomy HA, Ragab MA, Elantary MA, et al. New insights into Notch signaling as a crucial pathway of pancreatic cancer stem cell behavior by chrysin-polylactic acid-based nanocomposite. Discover Oncology. 2025; 16: 107.

[161] Gui K, Zhang X, Chen F, Ge Z, Zhang S, Qi X, et al. Lipid-polymer nanoparticles with CD133 aptamers for targeted delivery of all-trans retinoic acid to osteosarcoma initiating cells. Biomedicine & Pharmacotherapy. 2019; 111: 751–764.

[162] Ashrafizadeh M, Delfi M, Zarrabi A, Bigham A, Sharifi E, Rabiee N, et al. Stimuli-responsive liposomal nanoformulations in cancer therapy: pre-clinical & clinical approaches. Journal of Controlled Release. 2022; 351: 50–80.

[163] Gupta A, Jadhav SR, Colaco V, Saha M, Ghosh A, Sreedevi A, et al. Harnessing unique architecture and emerging strategies of solid lipid nanoparticles to combat colon cancer: a state-of-the-art review. International Journal of Pharmaceutics. 2025; 675: 125562.

[164] Kumar R, Dkhar DS, Kumari R, Divya, Mahapatra S, Srivastava A, et al. Ligand conjugated lipid-based nanocarriers for cancer theranostics. Biotechnology and Bioengineering. 2022; 119: 3022–3043.

[165] Jiang P, Xu C, Chen L, Chen A, Wu X, Zhou M, et al. EGCG inhibits CSC-like properties through targeting miR-485/CD44 axis in A549-cisplatin resistant cells. Molecular Carcinogenesis. 2018; 57: 1835–1844.

[166] Caliendo A, Camorani S, Ibarra LE, Pinto G, Agnello L, Albanese S, et al. A novel CD44-targeting aptamer recognizes chemoresistant mesenchymal stem-like TNBC cells and inhibits tumor growth. Bioactive Materials. 2025; 50: 443–460.

[167] Hegde M, Girisa S, BharathwajChetty B, Vishwa R, Kunnumakkara AB. Curcumin formulations for better bioavailability: what we learned from clinical trials thus far? ACS Omega. 2023; 8: 10713–10746.

[168] Liu Y, Shen Z, Zhu T, Lu W, Fu Y. Curcumin enhances the anti-cancer efficacy of paclitaxel in ovarian cancer by regulating the miR-9-5p/BRCA1 axis. Frontiers in Pharmacology. 2023; 13: 1014933.

[169] Duan H, Liu Y, Gao Z, Huang W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta Pharmaceutica Sinica B. 2021; 11: 55–70.

[170] Arcella A, Palchetti S, Digiacomo L, Pozzi D, Capriotti AL, Frati L, et al. Brain targeting by liposome-biomolecular corona boosts anticancer efficacy of temozolomide in glioblastoma cells. ACS Chemical Neuroscience. 2018; 9: 3166–3174.

[171] Huang X, Wan J, Leng D, Zhang Y, Yang S. Dual-targeting nanomicelles with CD133 and CD44 aptamers for enhanced delivery of gefitinib to two populations of lung cancer-initiating cells. Experimental and Therapeutic Medicine. 2020; 19: 192–204.

[172] Fan R, Tao X, Zhai X, Zhu Y, Li Y, Chen Y, et al. Application of aptamer-drug delivery system in the therapy of breast cancer. Biomedicine & Pharmacotherapy. 2023; 161: 114444.

[173] Lu R, Zhao G, Yang Y, Jiang Z, Cai J, Hu H. Inhibition of CD133 overcomes cisplatin resistance through inhibiting PI3K/AKT/mTOR signaling pathway and autophagy in CD133-positive gastric cancer cells. Technol Cancer Res Treat. 2019; 18: 1533033819864311.

[174] Cao X, Geng X, Zhang C, Li L. Decoding the role of cancer stem cells in digestive tract tumors: mechanisms and therapeutic implications (Review). International Journal of Oncology. 2025; 67: 61.

[175] Mirzaei R, Shafiee S, Vafaei R, Salehi M, Jalili N, Nazerian Z, et al. Production of novel recombinant anti-EpCAM antibody as targeted therapy for breast cancer. International Immunopharmacology. 2023; 122: 110656.

[176] Liu Y, Wang Y, Sun S, Chen Z, Xiang S, Ding Z, et al. Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside. Experimental Hematology & Oncology. 2022; 11: 97.

[177] Thakur A. Nano therapeutic approaches to combat progression of metastatic prostate cancer. Advances in Cancer Biology Metastasis. 2021; 2: 100009.

[178] Nair B, Menon A, Rithwik Kalidas M, Nath LR, Calina D, Sharifi-Rad J. Modulating the JAK/STAT pathway with natural products: potential and challenges in cancer therapy. Discover Oncology. 2025; 16: 595.

[179] Alam K. Nanocarrier-based drug delivery systems using microfluidic-assisted techniques. Advanced NanoBiomed Research. 2023; 3: 2300041.

[180] Izadiyan Z, Misran M, Kalantari K, Webster TJ, Kia P, Basrowi NA, et al. Advancements in liposomal nanomedicines: innovative formulations, therapeutic applications, and future directions in precision medicine. International Journal of Nanomedicine. 2025; 20: 1213–1262.

[181] Zhao J, Zhang C, Wang W, Li C, Mu X, Hu K. Current progress of nanomedicine for prostate cancer diagnosis and treatment. Biomedicine & Pharmacotherapy. 2022; 155: 113714.

[182] Zhang H, Chen H, Guo G, Lin J, Chen X, Huang P, et al. Nanotechnology in prostate cancer: a bibliometric analysis from 2004 to 2023. Discover Oncology. 2025; 16: 451.

[183] Abbasi R, Shineh G, Mobaraki M, Doughty S, Tayebi L. Structural parameters of nanoparticles affecting their toxicity for biomedical applications: a review. Journal of Nanoparticle Research. 2023; 25: 43.

[184] Vervaeke P, Borgos SE, Sanders NN, Combes F. Regulatory guidelines and preclinical tools to study the biodistribution of RNA therapeutics. Advanced Drug Delivery Reviews. 2022; 184: 114236.

[185] Zuzčák M, Trnka J. Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review). International Journal of Oncology. 2022; 61: 93.

[186] Costa C, Padrela L. Progress on drug nanoparticle manufacturing: exploring the adaptability of batch bottom-up approaches to continuous manufacturing. Journal of Drug Delivery Science and Technology. 2025; 111: 107120.

[187] Bi Y, Xie S, Li Z, Dong S, Teng L. Precise nanoscale fabrication technologies, the “last mile” of medicinal development. Acta Pharmaceutica Sinica B. 2025; 15: 2372–2401.

[188] Zhang J, Pan T, Lee J, Goldberg S, King SA, Tang E, et al. Enabling tumor-specific drug delivery by targeting the Warburg effect of cancer. Cell Reports Medicine. 2025; 6: 101920.