Dual Organelle-Targeted Near-Infrared Fluorescent Probe for Exploring Dynamic Nuclear Changes during Photodynamic Therapy

Observing the dynamic changes of important organelles during photodynamic therapy (PDT) can more intuitively elucidate the mechanism of action, but organelle-targeted fluorescent probes capable of accomplishing this task face challenges. Herein, we designed a dual organelle-targeted near-infrared fluorescent probe (<b>HJNu</b>) with a D-π-A structure to investigate PDT-induced dynamic nuclear changes and tumor ablation mechanisms. <b>HJNu</b> exhibited precise nuclear and lysosomal targeting capabilities, which enabled the tracing of nuclear changes during the cell division cycle. Upon laser irradiation, <b>HJNu</b> generated highly efficient O₂^-•, simultaneously inducing oxidative damage to both the nucleus and lysosomes, thereby significantly enhancing PDT efficacy. Confocal imaging captured characteristic apoptotic morphological features during PDT progression, including nuclear membrane invagination and chromatin condensation, which provided direct evidence for elucidating organelle damage mechanisms. This work both elucidated the critical role of dual organelle synergistic damage in tumor photodynamic ablation and furthered our understanding of the microscopic mechanisms of PDT through real-time fluorescence imaging of nuclear changes.