Sequential induction of ferroptosis and pyroptosis in cancer cells by lipid droplet-targeting AIE theranostics

Aggregation-induced emission (AIE) theranostics has received considerable attention because of its potential applications in bioimaging and photodynamic therapy (PDT). Herein, we report a series of phthalimide-based AIEgens that are selectively localized in lipid droplets (LDs) in cancer cells and simultaneously generate reactive oxygen species (ROS) under light irradiation. The enhanced photostability resulting from the AIE properties of LPSP2 enabled the long-term tracking of LDs during ferroptotic cell death triggered by LPSP2 under PDT conditions. As the irradiation time increased, the lipid peroxides generated by LPSP2 were transported from the LDs to the endoplasmic reticulum (ER), where oxidative stress activates NLRP3, leading to pyroptotic cell death. The spatiotemporal control of lipid peroxidation achieved by LPSP2 revealed sequential activation of ferroptosis followed by pyroptosis, depending on the irradiation duration. Our research demonstrates novel LD-targeted theranostics with unprecedented induction of ferroptotic and pyroptotic cell death under PDT, which will enrich our understanding of cancer cell death mechanisms toward a more efficient therapeutic strategy.