Shao Fengying, Han Jianyu, Tian Zhaoyan, Wang Zhi, Liu Songqin, Wu Yafeng
Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, State Key Laboratory of Digital Medical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
School of Energy and Environment, Southeast University, Nanjing 211189, China.
Biomaterials. 2023 Oct;301:122284. doi: 10.1016/j.biomaterials.2023.122284. Epub 2023 Aug 17.
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.
利用内源性钙上调线粒体内钙水平已成为线粒体功能障碍介导的肿瘤治疗的有力手段。然而，由于内源性钙转运的不可控性和非选择性，进入线粒体的钙是有限的。充分利用内源性钙以确保线粒体中足够的钙超载仍然是一个巨大的挑战。在此，我们巧妙地构建了一种细胞内钙定向转运通道，基于级联释放纳米平台ABT-199@脂质体/阿霉素@铁单宁酸（ABT@Lip/DOX@Fe-TA）将内源性钙从内质网（ER）选择性转运至线粒体。在肿瘤酸性微环境中，铁离子首先被释放并被单宁酸（TA）还原为亚铁以产生活性氧（ROS）。随后，在近红外光照射下，释放的ABT-199分子与ROS共同作用，促成内质网和线粒体之间形成IP3R-Grp75-VDAC1通道，从而使钙离子定向传递，线粒体内钙水平显著上调。协同产生活性氧和线粒体钙超载有效加剧线粒体功能障碍，从而实现高效的肿瘤抑制。这项工作为涉及内源性钙的肿瘤治疗提供了新的见解和有前景的途径。
