Organelle‐Targeted Photosensitizer‐Loaded Nanodiscs for Improved Tumor Photoimmunotherapy

ABSTRACT Photodynamic therapy (PDT) is a promising cancer treatment with minimal invasiveness and high selectivity, but its efficacy depends heavily on subcellular reactive oxygen species (ROS) localization. Although organelle‐targeted PDT can enhance antitumor effects, systematic evaluation and comparison of their photocytotoxicity, and photoimmunological activation capacity remain lacking. Herein, we synthesized four organelle‐targeted photosensitizers (PSs) using pyropheophorbide a (Ppa) as the core scaffold: Ppa‐Mit, Ppa‐Lys, Ppa‐ER, and Ppa‐Nuc, which target mitochondria, lysosomes, endoplasmic reticulum (ER), and nucleus, respectively. These PSs were then individually encapsulated into synthetic high‐density lipoprotein (sHDL) nanodiscs to yield PMN, PLN, PEN, and PNN. All nanodiscs achieved specific organelle targeting. Photocytotoxicity followed the order PLN > PMN > PNN > PEN, while PMN exhibited the optimal immunogenic cell death (ICD)‐inducing capacity by triggering robust secretion of damage‐associated molecular patterns (DAMPs). In vivo, PMN and PLN achieved complete, recurrence‐free tumor ablation, promoting infiltration of mature dendritic cells, and cytotoxic CD8 + T cells (expressing Granzyme B) to elicit strong antitumor immunity. This study identifies PMN and PLN as promising PDT agents and highlights mitochondria‐targeted and lysosome‐targeted PDT as a favorable approach for effective tumor photoimmunotherapy, providing guidance for the rational design of targeted PSs.