Tackling cancer stemness with nanotechnology in the era of precision medicine

Cancer stem cells (CSCs) represent a highly plastic therapy‐resistant tumor subpopulation that drives therapy resistance, disease recurrence, and metastasis. This review critically evaluates how nanotechnology‐based strategies are gaining traction in addressing key biological and translational barriers associated with CSC targeting in the context of precision oncology. On the diagnostic frontiers, nanoplatforms enable CSC detection through biomarker‐assisted and ‐independent functional imaging approaches, as well as liquid biopsy modalities that capture CSC‐associated circulating tumor cells, circulating tumor DNA (ctDNA), and extracellular vesicles, thereby supporting non‐invasive disease stratification and monitoring. Across therapeutic modalities, nanotechnology‐assisted delivery of mono‐ and combination chemo‐, radio‐, targeted, photothermal, photodynamic and sonodynamic therapies effectively sensitizes CSCs and eliminate them by enhancing intratumoral drug accumulation. Niche‐focused nanostrategies harness stimuli‐responsive activation of nanoparticles tailored to CSC‐associated microenvironmental cues, and modulate hypoxia, redox balance, metabolic plasticity, and stemness signaling as central mechanisms for disrupting CSC maintenance. Nanotechnology‐assisted immunotherapies, including checkpoint‐directed delivery, immune modulation, nano‐vaccines, and engineered cell strategies, represent emerging approaches to reprogram CSC‐immune interactions and enhance anti‐tumor immune responses. Nanoparticle physicochemical properties, pharmacokinetics, biodistribution, and immune interactions are critical parameters that govern their therapeutic efficacy and safety. Importantly, despite strong preclinical success, the clinical translation of nanotherapeutics remains constrained by limitations of preclinical models, regulatory hurdles, manufacturing complexity, and cost‐ineffectiveness. Overall, the evidence supports the view that rational, biomarker‐informed nanoplatform design, integrated with patient‐specific tumor features, represents a viable path toward precision CSC‐targeted therapies with improved clinical responses and durable cancer control.