A “dual lock-and-key” engineered intracellular synthesis for high-precision cancer therapy
Therapeutic biosynthesis is a promising strategy for precision cancer therapy, yet achieving controlled synthesis of abiotic materials within tumors remains challenging. Here, we report a “dual lock-and-key” system for tumor-specific intracellular synthesis. The precursor, termed “dual-lock,” is activated by two endogenously overexpressed enzymes—azoreductase (AzoR) and nitroreductase (NTR)—acting as “dual keys” in target cancer cells. This activation triggers a condensation reaction that produces fibrous mesh covalent organic polymers (Fm-COPs) in situ. Synthesized Fm-COPs effectively disrupt the cytoskeleton, inhibiting cell migration and invasion while inducing apoptosis. In vivo studies demonstrate that this strategy achieves specific tumor enrichment and deep penetration, leading to significant tumor growth inhibition (tumor inhibition rate >70%) without systemic toxicity, as evidenced by stable body weights and normal histopathology. The dual enzyme-responsive mechanism ensures high selectivity, and the small-molecule precursors facilitate efficient tumor penetration. This work presents a next-generation approach for high-precision cancer therapy, offering a biocompatible and autonomous strategy for intracellular synthesis.