Synergistic ROS generation and directional overloading of endogenous calcium induce mitochondrial dysfunction in living cells

Taking advantage of endogenous Ca 2+ to upregulate intramitochondrial Ca 2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca 2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca 2+ transport. It remains a great challenge to make the maximum use of endogenous Ca 2+ to ensure sufficient Ca 2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca 2+ directional transport channel to selectively transport endogenous Ca 2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@Fe III -tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment , Fe 3+ ions are firstly released and reduced by tannic acid (TA) to Fe 2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca 2+ ions are directionally delivered and intramitochondrial Ca 2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca 2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca 2+ -involved tumor therapies.