A label-free supramolecular nanoassembly triggers multi-organelle crosstalk-dependent metastasis inhibition via nuclear ROS-HDAC2 axis

Tumor metastasis, a leading cause of cancer-related mortality, presents a significant challenge due to its complex, multi-step nature and tumor cells' adaptability. Current targeted therapies often face limitations as tumor cells activate compensatory signaling pathways, leading to drug resistance. Here, we introduce a novel molecular drug pair of sorafenib (Sora) and curcumin (Cur) self-assembled into Sora-Cur@diploid nanoparticles (diNPs), which were transformed into label-free diNP@pharmaceutical dots (diNP@PDs) with enhanced fluorescence through a specialized formulation process, eliminating the need for chemical modification. diNP@PDs exhibit photoluminescence capability, simultaneously promoting cross-talk among lysosomes, mitochondria, and nuclei. This lysosomes-mitochondria-nuclei interaction induces perinuclear clustering of organelles, triggering nuclear reactive oxygen species (nuROS) generation. The nuROS epigenetically suppresses HDAC2 activity, inhibiting epithelial-mesenchymal transition (EMT) and tumor metastasis. By integrating multi-organelle targeting with molecular therapy, diNP@PDs offer an innovative strategy for both imaging and inhibiting tumor metastasis, highlighting the potential of interorganelle approaches in oncology.