Lipid Droplet-Targeted Near-Infrared II Type I AIE Photosensitizer Promotes Ferroptosis by Activating Lipophagy

Lipophagy, a selective autophagic pathway, maintains lipid homeostasis and contributes to ferroptosis by supplying lipid peroxidation substrates. However, organic photosensitizers that activate lipophagy to promote ferroptosis remain scarce. Herein, we developed a NIR-II emissive photosensitizer (MBTTD) targeting lipid droplets (LDs). Compared with its analogue MBTTA, stronger electron-withdrawing groups bathochromically shifted absorption/emission and tuned excited-state decay, enabling efficient type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency. MBTTD nanoparticles (NPs) localized to LDs upon cellular uptake. Upon 808 nm laser irradiation, MBTTD NP-mediated phototherapy disrupted LDs and induced Rab7-regulated lipophagy, releasing polyunsaturated fatty acids that underwent ROS-driven peroxidation, triggering extensive lipid peroxidation and ferroptosis. Concurrently, MBTTD-NP-mediated phototherapy triggered endoplasmic reticulum stress and apoptosis. MBTTD NPs showed favorable biocompatibility and potent therapeutic efficacy in multicellular tumor spheroids. In vivo studies revealed that MBTTD NPs enabled NIR-II imaging-guided phototherapy, suppressing 4T1 tumor growth without significant systemic toxicity.