DNA Programed Controllable Photodynamic Therapy with Positive‐Feedback Effect

Abstract Photodynamic therapy is gaining attention for its low invasiveness, minimal side effects, and potential to reduce resistance. However, the “always‐on” nature of photosensitizers can cause phototoxicity to normal tissues, requiring patients to avoid sunlight for long periods. While some methods can control PDT activation in tumors, they may reduce its effectiveness due to incomplete activation. In this study, a stimulus‐responsive nanoparticle is designed using Zr porphyrin carboxylate metal‐organic framework PCN‐224 and a DNA lock modified with Quencher and Apurinic/apyrimidinic sites (PCN‐QADNA). PDT is activated by Apurinic/apyrimidinic endonuclease 1, an endonuclease overexpressed in cancer cells, and further enhanced by positive feedback effect of cellular homeostasis regulation. PCN‐QADNA shows improved biocompatibility, enhanced cellular uptake, and a 93.5% tumor inhibition rate in tumor‐bearing mice after intravenous injection and light exposure, with no significant skin damage. This system enables controllable PDT with positive feedback, selectively targeting cancer cells and minimizing side effects. This study provides a promising approach for cancer therapy by improving targeting and treatment efficacy.