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

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