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 ( APT ), is designed and synthesized. APT 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. In vitro, the APT NPs have minimal dark cytotoxicity and significant light-induced cytotoxicity in MCF-7 cells, with an IC 50 of 4.61 μM. Importantly, multiomics analyses reveal a unique mechanism of action: APT 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. In vivo, 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.