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

Taking advantage of endogenous Ca²⁺ to upregulate intramitochondrial Ca²⁺ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca²⁺ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca²⁺ transport. It remains a great challenge to make the maximum use of endogenous Ca²⁺ to ensure sufficient Ca²⁺ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca²⁺ directional transport channel to selectively transport endogenous Ca²⁺ 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, Fe³⁺ ions are firstly released and reduced by tannic acid (TA) to Fe²⁺ 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 Ca²⁺ ions are directionally delivered and intramitochondrial Ca²⁺ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca²⁺ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca²⁺-involved tumor therapies.