Rational nanoengineering and personalized strategies for overcoming cancer stem cell-driven tumor heterogeneity.

Tumor heterogeneity, particularly the spatiotemporal heterogeneity driven by cancer stem cells (CSCs), is a key obstacle leading to therapy resistance, recurrence, and metastasis in malignant tumors. Although targeting CSCs holds the potential for eradicating tumors at their root, current therapies are limited by poor delivery efficiency and systemic toxicity. Nano drug delivery systems (NDDSs), with their designable physicochemical properties and intelligent responsive mechanisms, offer a revolutionary strategy to overcome these limitations. Moving beyond a conventional summary of NDDS applications, this review for the first time systematically integrates two cutting-edge perspectives: "rational carrier engineering" and a "personalized therapeutic framework." It elaborates on how design principles-such as surface engineering, biomimetic modification, and barrier-penetrating strategies-enable efficient targeting and drug delivery to CSCs via NDDSs. The review also critically evaluates the synergistic potential of combining NDDSs with multimodal therapies (e.g., photodynamic, sonodynamic, and magnetothermal therapy) as well as advanced modalities like gene editing and immunotherapy to comprehensively eradicate CSCs. More importantly, we propose a personalized NDDS framework tailored to tumor heterogeneity subtypes. This framework links deep molecular subtyping with adaptive carrier engineering and therapeutic feedback loops, providing a methodological blueprint for developing next-generation precision nanotherapies. Finally, the review discusses challenges in clinical translation, aiming to provide a new theoretical and strategic foundation for overcoming CSC-driven tumor heterogeneity and therapy resistance.