Construction of nucleus-targeted photosensitizer and highly effective photodynamic immunotherapy for cancer.

Abstract

Nucleus is the largest and most important organelle within eukaryotic cells, containing most of the cell's genetic material, DNA. It serves as the central hub for genetic regulation and metabolism, making it an ideal target for subcellular drug delivery. The development of nucleus-targeted photosensitizers allows for the rapid and effective destruction of critical components such as DNA within the nucleus. This achieves the goal of efficiently eliminating cancer cells. However, most organic molecules, including photosensitizers, cannot penetrate the nuclear membrane, making the design and synthesis of nucleus-targeted photosensitizers both significant and challenging. The authors have designed and synthesized a nucleus-targeted activatable photosensitive probe (CMT-I). In vitro spectral analyses demonstrate that CMT-I is specifically activated by ct-DNA, significantly enhancing fluorescence-a 49-fold increase is observed upon binding. Furthermore, under 590 nm light irradiation, CMT-I effectively generates ¹O₂. Molecular docking show that CMT-I selectively binds to DNA through hydrogen bonds and ᴨ-ᴨ conjugation. RNA sequencing experiments reveal that photodynamic therapy activates immunity within tumor cells, triggering an adaptive immune response. In vivo therapeutic experiments further verify the enhanced anti-tumor immunity of CMT-I, which is crucial for effectively eliminating immunologically cold tumors and highlights the potential of DNA-targeted photodynamic therapy in precise cancer treatment.