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.
Keywords: breast cancer; cuproptosis; endoplasmic reticulum stress; hollow CaCO3 nanoparticles; mitochondrial dysfunction.