Hollow Calcium/Copper Bimetallic Amplifier for Cuproptosis/Paraptosis/Apoptosis Cancer Therapy via Cascade Reinforcement of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

作者：Weijun Xu, Aili Suo, Abdalrheem Jarelnaby Musa Aldai, Yaping Wang, Jingjing Fan, Yuxiang Xia, Jiaxuan Xu, Zhexi Chen, Huichen Zhao, Mingzhen Zhang, Junmin Qian · 发表于：ACS Nano · 年份：2024 · DOI：10.1021/acsnano.4c11455 · 被引用次数：101 · 研究领域：Nanoplatforms for cancer theranostics、Advanced Nanomaterials in Catalysis、Nanoparticle-Based Drug Delivery

The endoplasmic reticulum (ER) and mitochondria are essential organelles that play crucial roles in maintaining cellular homeostasis. The simultaneous induction of ER stress and mitochondrial dysfunction represents a promising yet challenging strategy for cancer treatment. Herein, a hollow calcium–copper bimetallic nanoplatform is developed as a cascade amplifier to reinforce ER stress and mitochondrial dysfunction for breast cancer treatment. For this purpose, we report a facile method for preparing hollow CaCO 3 (HCC) nanoparticles by regulating the dissolution–recrystallization process of amorphous CaCO 3, and the amplifier D@HCC-CuTH is meticulously fabricated by sequentially coating disulfiram-loaded HCC nanoparticles with a copper coordination polymer and hyaluronan. In tumor cells, the dithiocarbamate–copper complex generated in situ by liberated disulfiram and Cu 2+ inhibits the ubiquitin–proteasome system, causing irreversible ER stress and intracellular Ca 2+ redistribution. Meanwhile, the amplifier induces mitochondrial dysfunction via triggering a self-amplifying loop of mitochondrial Ca 2+ burst, and reactive oxygen species augment. Additionally, Cu 2+ induces dihydrolipoamide S-acetyltransferase oligomerization in mitochondria, further exacerbating mitochondrial damage via cuproptosis. Collectively, ER stress amplification and mitochondrial dysfunction synergistically induce a cuproptosis–paraptosis–apoptosis trimodal cell death pathway, which demonstrates signi...