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Engineered nanoplatforms offer multifaceted strategies to overcome these barriers, including passive targeting, ligand-mediated active targeting, and membrane-mimetic camouflage for enhanced tumor accumulation. Stimuli-responsive and prodrug-based systems exploit tumor microenvironmental features, such as low pH, high glutathione, enzyme overexpression, and redox gradients, to achieve precise spatiotemporal drug release while avoiding efflux and inactivation. Codelivery of chemotherapeutics with sensitizers, immunotherapeutic agents, gene therapeutics, or physical stimuli enables synergistic intervention across multiple resistance pathways. Critically, CSC-targeted nanoplatforms selectively eliminate the root causes of tumor relapse and metastasis. 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