This review integrates advances in CSC biology with emerging nanomaterial-based strategies and discusses translational challenges and future directions for achieving durable cancer control through CSC-targeted nanotherapy.
Abstract
Therapeutic resistance remains a major barrier in cancer control and is increasingly recognized as a cancer stem cell (CSC)-driven process rather than a result of residual tumor survival. CSCs sustain tumor initiation, progression, and recurrence through coordinated intrinsic and extrinsic mechanisms, including enhanced drug efflux, cellular quiescence, hypoxia tolerance, efficient DNA damage repair, metabolic adaptation, and phenotypic plasticity. These features render CSCs largely refractory to conventional chemotherapy, radiotherapy, and many molecularly targeted therapies. Although extensive efforts have focused on inhibiting CSC-associated signaling pathways, such as Wnt/β-catenin, Notch, Hedgehog, and PI3K/AKT/mTOR, clinical translation has been limited by pathway redundancy, compensatory signaling, poor tumor penetration, and systemic toxicity. Nanomaterial-based therapeutic platforms represent a promising investigational strategy with potential to address these limitations enabling multi-level intervention against CSC survival architectures. Rationally engineered nanomaterials-including metallic, carbon-based, MXene, and polymeric nanocarriers-enable multi-functional targeting of cancer stem cell resistance by enhancing intracellular delivery, modulating hypoxic niches, and inducing catalytic or photothermal cytotoxicity. These platforms integrate controlled release, ligand-mediated targeting, and microenvironment responsiveness to overcome efflux, quiescence, and repair-mediated survival pathways in CSCs. Nanomaterials bypass ATP-binding cassette transporter-mediated drug efflux, induce cell-cycle-independent cytotoxicity, remodel hypoxic niches, overwhelm DNA repair capacity, and constrain phenotypic plasticity through coordinated pathway modulation. Photothermal and catalytic nanomaterials reduce or eliminate quiescent CSC populations. while ligand-functionalized nanocarriers targeting CSC markers such as CD44, CD133, and EpCAM enhance selective delivery and intracellular drug retention. This review integrates advances in CSC biology with emerging nanomaterial-based strategies and discusses translational challenges and future directions for achieving durable cancer control through CSC-targeted nanotherapy.
A comprehensive synthesis of the molecular and microenvironmental mechanisms underlying CSC-driven drug resistance is provided and emerging therapeutic strategies targeting CSC plasticity, niche interactions, metabolic adaptation, and immune evasion are critically discussed.
Hayam Hamdy, Youzhou Li, Chen Li et al.· Molecular Biomedicine· 0 citations
Tumor recurrence and therapeutic resistance remain major obstacles in effective cancer management, largely driven by a small but highly resilient subpopulation of cells known as cancer stem cells (CSCs). These cells possess self-renewal capacity, multipotency, and heightened resistance to chemotherapy, radiotherapy, and immunotherapy, enabling tumor regrowth and metastasis even after apparent clinical remission. Conventional anticancer strategies often fail to eradicate CSCs due to poor targeting specificity, systemic toxicity, and an inability to overcome the protective tumor microenvironment. Biomimetic nanoparticles have emerged as a promising precision nanomedicine strategy to address these limitations by emulating natural biological structures such as cell membranes, lipoproteins, exosomes, and extracellular matrix components. By inheriting biological functionalities including immune evasion, homotypic targeting, and receptor-specific interactions, biomimetic nanoparticles enable selective delivery of therapeutic payloads to CSC niches. This review comprehensively examines the biological basis of CSC-driven tumor recurrence, the design principles of biomimetic nanoparticles, and their application in selectively targeting CSCs. We discuss advances in membrane-coated, ligand-functionalized, and microenvironment-responsive biomimetic systems, highlight preclinical evidence of efficacy in preventing tumor relapse, and analyze translational challenges. Collectively, biomimetic nanoparticles represent a powerful platform for durable cancer control through precise CSC targeting.
Keywords: cancer stem cells; biomimetic nanoparticles; tumor recurrence; precision nanomedicine; targeted drug delivery.
Mutebi Mark· NEWPORT INTERNATIONAL JOURNA...· 0 citations
Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.
Mehreen Ahmed, A. Al-haidari, S. Agarwal et al.· Signal Transduction and Targ...· 0 citations
Plastic features of BCSCs are summarized, their roles in metastasis and multidrug resistance, microenvironmental regulation and relevant therapeutic targeting strategies are summarized and progress toward subtype-specific combination approaches is indicated.
Mu-Yao Li, Ying Zhou, Xin-Qi Liu et al.· Cancer Advances· 0 citations
Current insights into the molecular mechanisms underlying TME remodeling are summarized, including ECM mechanotransduction, hypoxia-driven signaling, hypoxia-driven signaling, epigenetic regulation, metabolic reprogramming, and extracellular vesicle-mediated communication.
Xiaoying Li, Shuang Dai, Dan Cao et al.· Frontiers in Cell and Develo...· 0 citations
Gastric cancer (GC) continues to be a significant global contributor to cancer-related mortality, primarily due to late-stage diagnoses, tumor heterogeneity, and the frequent emergence of therapeutic resistance. Despite advancements in surgical techniques, chemotherapy, targeted therapies, and immunotherapy, long-term survival rates remain unsatisfactory, underscoring the need for innovative, molecularly driven approaches. SiRNA has emerged as a promising gene-silencing tool capable of selectively downregulating oncogenic drivers and pathways associated with resistance via RNA interference. Preclinical studies using GC models demonstrate promising biological activity following siRNA-mediated suppression of various molecular targets - including CD44v6, Rac1, and ZNRD1-leading to reduced cell proliferation, inhibited migration and invasion, enhanced apoptosis, and increased chemosensitivity. However, the successful translation of siRNA-based strategies into clinical practice is fundamentally reliant on the development of efficient and safe delivery systems. Recent advancements in nanotechnology have enabled the development of multifunctional nanocarriers, including lipid-based nanoparticles, peptide-based systems, chitosanderived platforms, exosome-mimetic vesicles, layer-by-layer architectures, and stimuli-responsive theranostic nanoparticles. These engineered platforms are designed to enhance siRNA stability, improve tumor targeting, facilitate intracellular trafficking, and promote endosomal escape while minimizing off-target effects and immune activation. Preclinical findings suggest significant biological potential; however, additional research is required to address issues concerning biodistribution, safety, scalability, and regulatory standardization before clinical application. Overall, siRNA-based strategies may play a crucial role in the future development of precision-oriented therapeutic frameworks in GC research. Importantly, this review emphasizes the integration of molecular target selection with delivery system design in a GC-specific context. By systematically linking validated siRNA targets with corresponding nanocarrier strategies, this work provides a more application-oriented and translationally relevant perspective that is not typically addressed in conventional RNA interference or nanocarrier-focused reviews.
Gheysar Seifollahnezhad, B. Erdağ· Experimental oncology· 0 citations
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