Molecularly engineered lipid droplet-targeted NIR-II type I AIE photosensitizers trigger ferroptosis and apoptosis for cancer therapy

Abstract

Despite advancements in lipid droplet (LD)-targeted photosensitizers (PSs), critical challenges persist in achieving deep-tissue penetration, overcoming tumor hypoxic resistance, and coordinating multimodal cell death pathways. To address these limitations, a molecular engineering strategy was introduced to construct a series of aggregation-induced emission (AIE) PSs (MOITP, MOITM, and MOITT), which exhibited near-infrared (NIR) emission. The strong electron-withdrawing capability of the acceptor moiety in MOITT resulted in a bathochromic shift in absorption (606 nm) and NIR-II emission (1080 nm). Under 808 nm laser irradiation, MOITT exhibited the strongest type I reactive oxygen species generation and the highest photothermal conversion efficiency (η = 44%). Notably, MOITT nanoparticles (NPs) showed efficient cellular internalization and selective accumulation in LDs. Upon laser irradiation, phototherapy mediated by MOITT NPs initiated lipid peroxidation, triggering ferroptosis while synergistically inducing apoptosis. In vivo studies demonstrated that MOITT NPs enabled high-resolution NIR-II fluorescence imaging of blood vessels and effective imaging-guided phototherapy to eradicate tumors. This work establishes a novel paradigm for spatiotemporal control of cancer therapy through organelle-specific multimodal cell death integration.