Safe transportation and targeted destruction: Albumin encapsulated aggregation‐induced emission photosensitizer nanoaggregate for tumor photodynamic therapy through mitochondria damage‐triggered pyroptosis

Abstract 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.