Targeting mitochondrial-ER homeostasis via autophagy inhibition with celastrol-based nanotherapy for triple-negative breast cancer

The functional crosstalk between mitochondria and the endoplasmic reticulum (ER) serves as a critical adaptive mechanism in cancer cells, wherein mitochondrial damage-induced ER stress can paradoxically activate protective mitophagy to restore cellular homeostasis and limit therapeutic efficacy. To subvert this self-repair cycle and amplify immunogenic cell death (ICD), we engineered a mitochondria-targeted biomimetic nanoplatform (Cel-Ca/CQ@OMM) for tumor-selective co-delivery of Celastrol (Cel) and Chloroquine (CQ). The nanosystem leverages homologous mitochondrial membrane functionalization to achieve precise subcellular localization. Celastrol coordinates with calcium ions to form a complex (Cel-Ca) that induces Ca²⁺ overload and reactive oxygen species (ROS) burst, thereby damaging mitochondria and concomitantly triggering lipophagy as a compensatory survival response. The ER, upon contact with damaged mitochondria, activates mitophagy to clear these organelles. By suppressing autophagic flux, CQ simultaneously abrogates both reparative mitophagy and adaptive lipophagy. The resulting cumulative accumulation of damaged mitochondria and lipid droplets perpetuates ER-mitochondria interaction and imposes metabolic burden on the ER, establishing a vicious cycle that progressively amplifies cellular stress through positive feedback regulation, thereby steering the cell toward apoptotic elimination. This dual-inhibition intervention disrupts mitochondrial-ER homeostasis, leading to exacerbated ER stress, enhanced damage-associated molecular pattern (DAMP) release, and robust CD8⁺ T cell-mediated antitumor immunity. This study highlights the amplification of ICD by synergistically blocking the key adaptive pathways of mitophagy and lipophagy, providing a promising approach for Triple-negative breast cancer (TNBC) treatment.