Photosensitizer (PS) serves as the central element of photodynamic therapy (PDT). The use of common nanoparticles (NPs) for PDT has typically been rendered less effective by the undesirable aggregation-caused quenching (ACQ) effect, resulting in quenched fluorescence and reduced reactive oxygen species (ROS) generation that diminish the imaging quality and PDT efficacy. To overcome the ACQ effect and to enhance the overall efficacy of PDT, herein, integrin α_νβ₃-targeted organic nanodots for image-guided PDT were designed and synthesized based on a red emissive aggregation-induced emission (AIE) PS.

Background: Aggregation-induced emission (AIE)-based photodynamic therapy (PDT) represents a promising strategy for cancer treatment for its capacity to activate specific cell death pathways through pronounced oxidative stress. While the activation of specific death pathways has been correlated with PDT efficiency and overall effect, the systematic coordination of oxidative stress across different cell death modalities to amplify therapeutic effects remains unexplored. Current research lacks systematic investigation into how oxidative stress coordinates multiple cell death pathways to amplify therapeutic outcomes of PDT.

Photodynamic therapy is a highly recommended alternative treatment for solid tumors, such as cutaneous or luminal tumors, in clinical practice. However, conventional photosensitizers (PSs) often induce undesirable phototoxic effects because of their normal tissue distribution and a reduction in antitumor effects resulting from aggregation‐caused quenching effects. The present study developed a novel nano‐formulated aggregation‐induced emission (AIE)‐characteristic PS, nab‐TTVPHE, which is composed of human serum albumin as a carrier and TTVPHE as a therapeutic agent, as a more effective cancer treatment with lower phototoxic effects. Notably, the reactive oxygen species generated by TTVPHE were shielded by the nanoaggregate structure, and the photodynamic activity was after nanostructure dissociation. Nab‐TTVPHE was actively internalized in tumor cells via secreted protein, acidic and rich in cysteine and released to form nanoaggregates. TTVPHE accumulated in mitochondria, where it triggered mitochondrial damage under light irradiation via its photodynamic activity and induced pyroptosis via the caspase‐3/gasdermin E (GSDME) signaling pathway to kill tumor cells. Therefore, this nano‐formulated AIE‐characteristic PS provides an innovative strategy for cancer treatment with lower phototoxic effect and the ability to boost potential antitumor immunity via GSDME‐mediated pyroptosis.

An AIE-active photosensitizer, TTVPHE , can fast penetrate into cancer cells and efficiently trigger mitochondria-dependent apoptotic pathway with self-monitoring ability.

Photodynamic therapy (PDT) has emerged as a promising locoregional therapy of hepatocellular carcinoma (HCC). The utilization of luminogens with aggregation-induced emission (AIE) characteristics provides a new opportunity to design functional photosensitizers (PS). PSs targeting the critical organelles that are susceptible to reactive oxygen species damage is a promising strategy to enhance the effectiveness of PDT. In this paper, a new PS, 1-[2-hydroxyethyl]-4-[4-(1,2,2-triphenylvinyl)styryl]pyridinium bromide (TPE-Py-OH) of tetraphenylethylene derivative with AIE feature was designed and synthesized for PDT. The TPE-Py-OH can not only simultaneously target lipid droplets and mitochondria, but also stay in cells for a long period (more than 7 days). Taking advantage of the long retention ability of TPE-Py-OH in tumor, the PDT effect of TPE-Py-OH can be activated through multiple irradiations after one injection, which provides a specific multiple light-activated PDT effect. We believe that this AIE-active PS will be promising for the tracking and photodynamic ablation of HCC with sustained effectiveness.

Surgical resection is the preferred option for hepatocellular carcinoma (HCC), but surgical navigation technology using indocyanine green still has some drawbacks such as non‐specific imaging, thus it is very important to develop new fluorescence imaging technology. All‐ cis hexaphenyl‐1,3‐butadiene derivative (ZZ‐HPB‐NC) with aggregation‐induced emission (AIE) feature has been reported to be quickly turned‐on fluorescent response in the intraoperative frozen‐section slides of HCC. However, the probe did not respond to normal liver tissue around HCC. In order to enhance the diagnostic rate and elucidate the response mechanism, all‐ trans configuration EE‐HPB‐NC, was furtherly synthesized. Within two minutes, non‐cancer tissues could be fluorescently labeled by EE‐HPB‐NC by spraying, showing the same effect with ZZ‐HPB‐NC to HCC. The results indicated that the configuration‐induced cross‐identification fluorescence imaging strategy was achieved through the combination of ZZ‐ and EE‐HPB‐NC. Then the mechanism of HPB‐NC localization in HCC lesions was explored, and the binding of HPB‐NC with specific proteins in cells resulted in the AIE effect to label HCC cells. On this basis, the accuracy of specific fluorescence imaging for HCC was further verified on the mouse hepatic neoplasm models, indicating that it has clinical application potential for surgical fluorescence real‐time navigation.