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

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 CaCO3 (HCC) nanoparticles by regulating the dissolution–recrystallization process of amorphous CaCO3, 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 Cu2+ inhibits the ubiquitin–proteasome system, causing irreversible ER stress and intracellular Ca2+ redistribution. Meanwhile, the amplifier induces mitochondrial dysfunction via triggering a self-amplifying loop of mitochondrial Ca2+ burst, and reactive oxygen species augment. Additionally, Cu2+ 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 significant efficacy in suppressing tumor growth. This study presents a paradigm for synchronously inducing subcellular organelle disorders to boost cancer multimodal therapy.