Concurrent Ferroptosis and Pyroptosis Induced by a Dual-Organelle-Targeted Type I/II AIE Photosensitizer for Bladder Cancer Immunotherapy.

The therapeutic efficacy and cell death modalities of photodynamic therapy (PDT) highly depend on reactive oxygen species (ROS) generation mediated by photosensitizers (PSs) and their subcellular localization. However, research exploring the potential mechanisms underlying ROS-induced ferroptosis and pyroptosis remains scarce. In this study, we develop a type I/II aggregation-induced emission photosensitizer (AIE PS), DFTBPPY (DY), that primarily accumulates in the endoplasmic reticulum (ER) and lipid droplets (LDs) to disrupt lipid homeostasis and induce concurrent cell death against bladder cancer. DY is selectively endocytosed by tumor cells and anchors in both ER and LDs. Upon laser irradiation, in situ DY can generate ROS to initiate oxidative stress and damage the functions of the ER and LDs. This disruption thereby initiates a lipid peroxidation-cascading cell death pathway involving ferroptosis, pyroptosis, and immunogenic cell death (ICD), leading to potent antitumor effects. Our findings demonstrate that DY, as a dual-organelle-targeted PS, enhances therapeutic outcomes by orchestrating concurrent cell death mechanisms, which represents a promising alternative therapeutic strategy and highlights the potential of lipid imbalance in concurrent cell death for bladder cancer.