A dynamic assembly-based logic-gated tetrahedral DNAzyme prodrug for mitochondrial metabolic intervention and enhanced chemodynamic therapy

Chemodynamic therapy (CDT) offers an innovative strategy for tumor treatment, but its efficacy and selectivity are significantly hampered by limited intratumoral Fenton reaction efficiency and a lack of organelle-level precision. To this end, we developed a dynamic assembly-based logic-gated intelligent proximity-enhanced tetrahedral-scaffold DNAzyme prodrug (PETS). By enabling programmable activation and sequential control of key biochemical events (including targeting, assembly, therapy initiation), the PETS achieves organelle-precise metabolic reprogramming intervention and CDT. PETS forms linear assemblies in tumor cells via logic-gated recognition of PTK7 and miRNA, then targets mitochondria through triphenylphosphonium (TPP). This disrupts mitochondrial metabolism, inhibits tumor cell proliferation and migration, and induces oxidative stress to generate substantial ROS, providing substrates for the Fenton-like reaction. Meanwhile, dynamic assembly activates PETSzyme, which produces abundant •OH via a highly efficient Fenton-like reaction, causing significant tumor cell killing. Compared with traditional G4 DNAzyme, PETSzyme exhibits an approximately four-fold enhancement in catalytic performance under the synergistic effects of proximity enhancement and the tetrahedral scaffold. In tumor-bearing mouse models, PETS demonstrated advantages in targeted delivery, controllable activation, minimal side effects, and enhanced CDT efficacy. This study provides a unique and promising platform for highly efficient and safe CDT, holding substantial potential for future clinical translation and improved cancer therapy.