Logic‐Responsive Superspherical Nucleic Acid Enables Tumor‐Specific Multiplexed Gene Silencing for Efficient Cancer Therapy

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.