Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, and treatment options for advanced disease are still inadequate. Photodynamic therapy (PDT) offers a minimally invasive alternative by generating cytotoxic reactive oxygen species (ROS) upon photosensitizer activation, yet its efficacy is limited by the hypoxic tumor microenvironment. We developed a novel near-infrared II (NIR-II) aggregation-induced emission (AIE) photosensitizer, DB-PTZ, by combining the electron donor phenothiazine with the electron acceptor malononitrile and introducing conjugated peripheral groups to enhance electron delocalization. DB-PTZ nanoparticles, prepared via 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-2000 (DSPE-PEG2000) encapsulation, exhibited uniform size (∼45 nm), negative surface charge (∼35.82 mV), high photothermal conversion efficiency (∼49%), robust stability, minimal hemolysis (<4% at 25 μg/mL), and efficient, time-dependent cellular uptake with lysosomal escape. Under 808 nm laser irradiation (0.8 W·cm–2), DB-PTZ significantly increased intracellular ROS, induced apoptosis (44.74%), and inhibited the proliferation, migration, and invasion of HCC cells. In vivo, DB-PTZ selectively accumulated in tumors, providing potent growth suppression without measurable systemic toxicity. These results establish DB-PTZ as a hypoxia-tolerant NIR-II AIE photosensitizer with dual photothermal–photodynamic activity, offering a promising platform for precise, image-guided theranostics in HCC.