A Tumor‐Specific Cascade‐Activating Smart Prodrug System for Enhanced Targeted Therapy

Abstract Developing intelligently targeted drugs with low side effects is urgent for cancer treatment. Toward this goal, a tumor‐specific cascade‐activating smart prodrug system consisting of a G‐quadruplex(G4)‐modulated tumor‐targeted DNA vehicle and a well‐designed cellular stimuli‐responsive ligand‐drug conjugates (LDCs) is proposed. An original “donor–acceptor” binary fluorescent ligand, with ultrahigh affinity, brightness, and photostability, is engineered to tightly bind G4 structures and significantly improve the nuclease resistance of the DNA vehicle, which serves as a bridge contributing to the construction of the prodrug system, named ApG4/LDCs. Sodium nitroprusside and doxorubicin are loaded into ApG4/LDCs in one pot and generate nitric oxide and superoxide anion in response to cancer cellular environments, which in cascade generates peroxynitrite to cause DNA damage while promoting the self‐monitored drug release to achieve enhanced targeted therapy. Such a cascade activation and self‐reinforcement process is executed only when the prodrug system targets the tumor tissue followed by cell uptake, showing significant antitumor efficacy and greatly weakening the damage to normal tissues. Given the unique features, the innovative strategy for prodrug design may open a new door to precision disease treatment.