Blocking Spatiotemporal Crosstalk between Subcellular Organelles for Enhancing Anticancer Therapy with Nanointercepter.

The spatiotemporal characterization of signaling crosstalk between subcellular organelles is crucial for the therapeutic effect of malignant tumors. Blocking interactive crosstalk in this fashion is significant but challenging. Herein, we report a communication interception strategy, which blocks spatiotemporal crosstalk between subcellular organelles for cancer therapy with underlying molecular mechanisms. Briefly, amorphous-core@crystalline-shell Fe@Fe 3 O 4 nanoparticles (ACFeNPs) were fabricated to specifically block the crosstalk between lysosomes and endoplasmic reticulum (ER) by hydroxyl radicals generated along with their trajectory through heterogeneous Fenton reaction. ACFeNPs initially entered lysosomes and triggered autophagy, then continuous lysosomal damage blocked the generation of functional autolysosomes which mediated ER-lysosome crosstalk, thus the autophagy was paralyzed. Thereafter, released ACFeNPs from lysosomes induced ER stress. Without the alleviation by autophagy, ER stress-associated apoptotic pathway was fully activated, resulting in remarkable therapeutic effect. This strategy provides a wide venue for nanomedicine to exert biological advantages and confers new perspective for the design of novel anticancer drugs. This article is protected by copyright. All rights reserved.