Mitochondria‐Targeted Photodynamic and Mild‐Temperature Photothermal Therapy for Realizing Enhanced Immunogenic Cancer Cell Death via Mitochondrial Stress

Abstract Induction of immunogenic cell death (ICD) represents a robust therapeutic strategy for cancer treatment. However, only a few ICD inducers are currently available and many of them take effect based on traditional endoplasmic reticulum (ER) stress rather than mitochondrial stress. Besides, mitochondrion is closely related to ER and drug delivery via mitochondrial targeting usually shows a higher efficiency and cytotoxicity than that via ER targeting, which inspires to explore the ICD effect of cancer cells through mitochondrial stress. Herein, a mito‐missile that can realize not only mitochondria‐targeted photodynamic therapy (PDT)/mild‐temperature photothermal therapy (MTPTT) but also ICD‐induced cancer immunotherapy is constructed. The mito‐missile (termed DIH) is prepared by coating dc‐IR825 (a mitochondrion‐targeting cyanine dye)‐loaded polyamidoamine dendrimer with hyaluronic acid. dc‐IR825 can precisely target mitochondria and produce reactive oxygen species (ROS) and mild heat upon near‐infrared (NIR) light irradiation, inducing mitochondrial damage and mitochondrial stress‐caused enhanced ICD. By combining PDT, MTPTT, and ICD‐induced immunotherapy, the DIH mito‐missile can efficiently inhibit tumor growth and even eradicate tumors. This study develops a dendrimer‐based nanoplatform for realizing mitochondrion‐acting PDT/MTPTT as well as mitochondrial stress‐induced potentiated ICD, which may provide a guideline for designing effective ICD inducers in the future.