Iron Oxide Nanoparticles as Autophagy Intervention Agents Suppress Hepatoma Growth by Enhancing Tumoricidal Autophagy

The combined treatment with nanoparticles and autophagy inhibitors, such as chloroquine (CQ) and hydroxychloroquine (HCQ), is extensively explored for cancer therapy. However, the toxicity of autophagy inhibitors and their unselective for tumoricidal autophagy have seriously hindered the application of the combined treatment. In this study, a carboxy‐functional iron oxide nanoparticle (Fe2O3@DMSA) is designed and identified to significantly exert an antitumor effect without adding CQ or HCQ. Further investigation indicates that the effective inhibition effect of Fe2O3@DMSA alone on hepatoma growth is triggered by inhibiting the fusion of autophagosomes and lysosomes to enhance tumoricidal autophagy, which is induced by intracellular iron‐retention‐induced sustained reactive oxygen species (ROS) production. Furthermore, in two hepatoma‐bearing mouse models, Fe2O3@DMSA alone effectively suppresses the growth of tumors without obvious toxic side effects. These studies offer a promising strategy for cancer therapy. Carboxy‐functional iron oxide nanoparticles (Fe2O3@DMSA) trigger intracellular iron‐retention‐induced sustained reactive oxygen species (ROS) production to activate autophagy but block the fusion of autophagosomes and lysosomes, which efficiently inhibits hepatoma growth through enhancing tumoricidal autophagy in vitro and in vivo. Fe2O3@DMSA shows potential clinical application for hepatoma therapy.