Lipid droplets-mediated delivery of curcumin for targeted mitochondrial photodynamic therapy

Lipid droplets (LDs), intracellular organelles characterized by a phospholipid monolayer shell enclosing a neutral lipid core, serve as ideal reservoirs for lipophilic drugs. By exploiting the β-oxidation pathway, lipids stored in LDs can be transported to mitochondria, enabling targeted drug delivery. Notably, by altering the culture conditions, the particle size of LDs within cells can be regulated, demonstrating their suitability for development as drug carriers. Curcumin (CUR), a natural lipophilic photosensitizer, exhibits considerable potential for applications in photodynamic therapy (PDT). We confirmed that exogenous LDs can be taken up by cells and effectively localized around mitochondria. Then we exploited LDs as drug carriers to develop curcumin-loaded LDs (CUR-LDs) that capitalize on the intrinsic interplay between LDs and mitochondria to enable targeted mitochondrial delivery for photodynamic therapy. In vitro, CUR-LDs irradiated with 450 nm light (100 mW/cm 2 , 5 min) significantly increased intracellular reactive oxygen species (ROS) levels (5.2-fold), together with inactivation of mitochondrial cytochrome oxidase and reduced mitochondrial membrane potential (JC-1 red/green ratio: from 26.50 ± 4.81 to 1.76 ± 0.04), and ultimately promoted apoptotic cell death. These results highlight LDs as promising mitochondria-targeted drug carriers and demonstrate an effective curcumin formulation with potential applications in cancer therapy.