Proteolysis‐triggered RNA Interference for Mitochondrial Iron Dyshomeostasis to Activate Antitumor Immunity in Hepatic Carcinoma

and the loaded siRNA. siRNA-mediated ENO1-targeted knockdown would upregulate the mitochondrial iron transport channel through the ENO1-IRP1-Mfrn1 pathway, which subsequently leads to mitochondrial iron overload and the increase of detrimental mitochondrial reactive oxygen species (ROS), thereby triggering severe mitochondria destruction and causing mass death of tumor cells. Noteworthily, it is found that cRGD-VFs-mediated mitochondrial iron overload can activate powerful antitumor immunity by upregulating immune-related pathways to eliminate tumors, achieving notable tumor suppression in multiple murine liver cancer models, which represents a promising strategy of disturbing mitochondrial iron homeostasis for potentiating antitumor immunotherapy.