DNA Nanostructures for Overcoming Cancer Drug Resistance: Mechanisms, Therapeutic Strategies, and Translational Challenges

ABSTRACT Cancer drug resistance, a major cause of chemotherapy failure, arises from multiple interconnected barriers, including reduced intracellular drug accumulation, enhanced drug efflux, adaptive survival signaling, increased DNA repair, and redox or metabolic remodeling. To address these limitations, recent advances in programmable DNA nanostructures have provided new opportunities for constructing multifunctional nanotherapeutic platforms. This review examines how the structural characteristics of DNA nanostructures influence drug delivery, molecular regulation, and resistance modulation, and analyzes how different DNA nanoplatforms, including tetrahedral framework nucleic acids, DNA origami, DNA nanoflowers, spherical nucleic acids, and hybrid DNA assemblies, contribute to therapeutic regulation. It then highlights their applications in overcoming major resistance‐associated barriers, such as inefficient cellular uptake, drug efflux, apoptosis evasion, DNA repair activation, and biochemical adaptation. Finally, it discusses the challenges in DNA nanostructure‐based cancer therapy and proposes future directions for improving stability, intracellular delivery, tumor accumulation, immune safety, and scalable manufacturing. These advances suggest that DNA nanostructures may serve as next‐generation programmable nanomedicine platforms for multilevel intervention against cancer drug resistance.