Heavy-atom-effect enhanced singlet oxygen generation of carbon dots for lipid-targeting tumor photodynamic therapy inducing ferroptosis.

Carbon dots (CDs) have garnered significant attention in the field of tumor photodynamic therapy (PDT) in recent years, attributed to their superior optical properties and favorable biocompatibility. In the research on PDT inducing tumor ferroptosis via lipid peroxidation (LPO), pursuing novel CDs-based photosensitizers (PSs) with higher ROS yield and subcellular structure-lipid targeting capabilities remains a significant challenge. This study presents the design and synthesis of heavy-atom-effect-enhanced CDs PSs specifically tailored for lipid-targeting PDT inducing tumor ferroptosis. Initially, red-emitting CDs (RCDs) doped with fluorine (F), chlorine (Cl), and bromine (Br) were synthesized. Notably, bromine-doped RCDs (Br-RCDs) exhibited remarkable singlet oxygen (O) generation capacity, attributed to the heavy-atom effect. Subsequent cellular experiments revealed that Br-RCDs were efficiently internalized by cells and specifically targeted to lipid droplets and cell membranes. Upon light exposure, Br-RCDs generated substantial O, inducing tumor cells LPO accumulation, glutathione peroxidase 4 (GPX4) protein expression downregulation and mitochondrial damage, thereby causing cell ferroptosis. Furthermore, in vivo studies corroborated the notable antitumor efficacy of Br-RCDs-mediated PDT in xenograft tumor models, highlighting its potent ability to induce tumor ferroptosis and exceptional biocompatibility. This research contributes vital insights into the design and synthesis of organelle-targeting, heavy-atom-doped CDs as high-performance photosensitizers, thereby enabling efficient induction of tumor ferroptosis via PDT.