NIR‐II Imaging‐Guided Mitochondrial‐Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy

Abstract Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial‐targeting phototheranostic system, FE‐T nanoparticles (FE‐T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE‐T NPs are engineered by encapsulating the near‐infrared (NIR) absorbed photosensitizer IR‐FE‐TPP within amphiphilic copolymer DSPE‐SS‐PEG‐COOH for high‐performing with simultaneous mitochondrial‐targeting, near‐infrared II (NIR‐II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR‐FE‐TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE‐T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial‐targeting with FE‐T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE‐T NPs provide an effective mitochondrial‐targeting phototheranostic nanoplatform for imaging‐guided tumor therapy.