Lipid droplet-targeted NIR AIE photosensitizer evoking concurrent ferroptosis and apoptosis

Lipid droplets (LDs), which are the hubs of lipid metabolism, play a critical role in maintaining cellular energy homeostasis. The construction of advanced photosensitizers (PSs) capable of manipulating LD-mediated cell fate regulation is highly desirable though rarely reported. In this study, a near-infrared emissive PS (DPCMP) with LDs specificity was synthesized and successfully applied to induce ferroptosis and apoptosis. DPCMP exhibited typical aggregation-induced emission characteristics owing to its twisted molecular conformation. Excellent biocompatibility and suitable lipophilicity allowed DPCMP to specifically stain the LDs in living cells. Under white light illumination, the DPCMP displayed potent reactive oxygen species (ROS) generation capacity through both type I and II photochemistry. The massive accumulation of lethal ROS generated by DPCMP-mediated photosensitization initiated lipid peroxidation, impaired cellular redox homeostasis, and led to endoplasmic reticulum oxidative stress, ultimately inhibiting cellular proliferation via concurrent ferroptosis and apoptosis in both living cancer cells and multicellular tumor spheroids. The coumarin-based lipophilic AIE photosensitizer DPCMP was developed to precisely stain the lipid droplets in living cells. The potent reactive oxygen species generation capacity enabled DPCMP to initiate lipid peroxidation, impair endoplasmic reticulum homeostasis, and ultimately inhibit cancer cell proliferation by inducing concurrent ferroptosis and apoptosis. image