Dual-Organelle-Targeted Organic Small-Molecule Photosensitizers in Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) has emerged as a minimally invasive and clinically adaptable strategy for cancer treatment, leveraging photosensitizer (PS) activation by light to generate reactive oxygen species (ROS) that destroy malignant cells. However, the therapeutic efficacy of PDT critically depends on the subcellular localization of PSs, as the generated ROS have limited diffusion ranges and lifetimes. In recent years, the design of PSs capable of simultaneously targeting multiple organelles has attracted growing attention. Dual-organelle-targeted PSs can induce synergistic damage in vital subcellular compartments, disrupt cross-organelle signaling networks, and overcome tumor resistance mechanisms. This review summarizes recent progress in the development of small-molecule PSs with dual-organelle targeting capabilities, focusing on mitochondria–nucleus, mitochondria–endoplasmic reticulum, mitochondria–lysosomes, mitochondria–plasma membrane, mitochondria–lipid droplets, lipid droplets–endoplasmic reticulum, and lysosomes–lipid droplets. We discuss the design principles, photophysical mechanisms, and biological consequences of dual-organelle photodamage, emphasizing how such strategies enhance PDT precision, efficacy, and immunogenic potential. Finally, we highlight current challenges and outline future directions toward rational molecular design and clinical translation of dual-targeted PDT agents.