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 s uper s pherical n ucleic a cid (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.