AIE-Active Photosensitizer APT NPs with Type I/II ROS Generating Orchestrate the DDIT4-Centric Gene-Metabolite Axis in Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising strategy for tumor treatment; however, the oxygen adaptation of conventional photosensitizers, coupled with the elusive mechanism, has greatly hindered their further development. Here, a novel organic aggregation-induced emission (AIE) active Schiff base photosensitizer, namely, 2-(((5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)methylene)amino)-4-phenylthiophene-3-carbonitrile (), is designed and synthesized. nanoparticles (NPs) efficiently generate both type I (hydroxyl radicals and superoxide anions) and type II (singlet oxygen) reactive oxygen species (ROS), enabling strong phototoxicity even under hypoxic conditions. , the NPs have minimal dark cytotoxicity and significant light-induced cytotoxicity in MCF-7 cells, with an IC of 4.61 μM. Importantly, multiomics analyses reveal a unique mechanism of action: NPs induce the upregulation of the stress-responsive gene DNA damage-inducible transcript 4 (DDIT4), which inhibits the mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway. This inhibition establishes a cohesive gene-metabolite regulatory axis, triggers the downregulation of key oncogenic drivers (FBJ osteosarcoma sarcoma viral oncogene homologue (FOS) family and B-cell cell lymphoma-2 (Bcl-2)) and the disruption of valine/leucine/isoleucine biosynthesis, leading to cell cycle arrest and apoptosis. , the MCF-7 tumor-bearing mouse model confirms potent antitumor efficacy without significant side effects. This work not only introduces a hypoxia-insensitive PDT agent but also provides novel insights into the mechanistic interaction between transcriptional and metabolic regulation in PDT, highlighting the potential of AIE-active materials for cancer therapy.