Gene-targeted therapies are of considerable interest for targeting multiple "undruggable" oncogenes. However, their therapeutic efficacy is largely hampered by off-target toxicity and inherent tumor heterogeneity. Herein, we describe a logic-responsive superspherical nucleic acid (SSNA) with on-demand, activatable functionality that enables tumor-specific multiplexed gene silencing for efficient cancer therapy. The SSNA architecture features a nuclease-resistant spherical nucleic acid core densely coated with a Y-shaped DNA circuit shell that selectively responds to apurinic/apyrimidinic endonuclease 1 (APE1), a biomarker overexpressed in tumor cytoplasm. Upon intracellular APE1-triggered shell disassembly, the SSNA enables the controlled release of split antisense oligonucleotides targeting thymidine kinase 1 (TK1) mRNA and DNAzymes that cleave survivin mRNA. Both in vitro and in vivo results demonstrated robust dual-gene silencing of TK1 and survivin at both transcriptional and translational levels, accompanied by exceptional tumor specificity and minimal off-target effects. Notably, in a murine MCF-7 xenograft model, SSNA significantly suppressed tumor growth and extended median survival by an impressive 70% compared to single-target interventions. By integrating tumor-specific activation with multiplexed gene silencing, such an SSNA platform offers a powerful and versatile approach for advancing next-generation precision cancer therapies.
Xian-Ming Guo, Mei-Ling Zhao, Xia Yang et al.· Angewandte Chemie· 0 citations
Leveraging the predictability of Watson–Crick base pairing and the programmability of nucleic-acid structures, DNA nanodevices can be rationally designed into diverse architectures that incorporate functional motifs such as aptamers and DNAzymes. These multifunctional constructs enable the integration of target recognition, signal transduction, and amplification within a single framework, facilitating versatile biomolecular sensing. However, translating conventional DNA nanodevices into practical applications within complex biological samples remains challenging due to their high susceptibility to nuclease degradation, which compromises structural integrity and leads to signal leakage. Additionally, the low abundance of target analytes and the crowded nature of biological fluids significantly reduce molecular collision frequency and slow interfacial reaction kinetics, thereby resulting in poor sensitivity and a high detection limit. Therefore, developing next-generation DNA nanodevices with enhanced structural stability and improved reaction efficiency is crucial for their practical use in real biological environments.
Confinement refers to the spatial restriction of molecules, reactants, or reaction interfaces within nanometer-sized domains, where their physicochemical behaviors differ markedly from those in bulk solutions. Under confined conditions, reactive components can be shielded from external interference, thus enhancing molecular stability. Moreover, confined environments can locally enrich reactants and reduce the configurational entropy of reaction components, greatly improving the thermodynamic and kinetic efficiency of molecular interactions. Thus, integrating confinement effects into DNA nanodevices offers a promising strategy for the synergistically enhancing both structural robustness and sensing performance in complex biological samples.
In this Account, we describe our recent efforts to design and develop spatially confined DNA nanodevices aimed at improving molecular sensing in real biological samples. By engineering the molecular interaction interface of DNA nanodevices through confinement strategies, we have developed four representative classes of such materials, that are cavity-confined, surface-confined, topological structure-confined, and network-confined DNA nanodevices. We systematically explore their advanced applications in biomarker sensing within biological samples and discuss the underlying mechanisms responsible for the enhanced structural stability and the analytical performance, including sensitivity, limit of detection, and reaction kinetics. The experimental progress summarized in this Account suggests that confinement strategy could serve as a versatile design principle for engineering DNA nanodevice interfaces, thereby advancing practical biosensing applications in complex biological environments.
Jie Liu, Liu-Qing Tan, Xiuli Tao et al.· Accounts of Materials Resear...· 0 citations
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