An electro-ferroptotic nanoammunition enables image-guided, spatiotemporally controlled cancer ferroptosis induction via irreversible electroporation

An IRE-triggered electro-ferroptotic nanoammunition (EFN) has been developed, which enables controlled release of Fe 2+ ions for effective cancer treatment. The EFN treatment effectively induces ferroptosis in cancer cells and expands the therapeutic range of IRE . The synergistic effect of EFN and IRE leads to significant inhibition of tumor growth and activation of immune cells , providing a promising strategy for personalized cancer ferroptotic therapy. • An electro-ferroptotic nanoammunition (EFN) for ferroptosis induction via IRE. • EFN facilitates cytosolic Fe 2+ accumulation for ferroptosis and immunotherapy. • IRE-triggered Fe 2+ release can be readily monitored by magnetic resonance imaging. Ferroptosis, an iron-dependent regulated cell death pathway, has emerged as a promising modality for cancer therapy. However, current iron-based ferroptosis inducers, which trigger the Fenton reaction and release Fe 2+ , face challenges associated with limited cytosolic Fe 2+ accumulation, leading to suboptimal ferroptosis induction. Herein, we report an electro-ferroptotic nanoammunition (EFN) composed of iron oxide nanoassembly (IONA) and ascorbic acid-loaded liposomes (Lip-AA) that enables image-guided, spatiotemporally controlled ferroptosis induction via irreversible electroporation (IRE) for enhanced cancer ferroptotic therapy. The IONA and Lip-AA form stable complexes through electrostatic interactions. Upon IRE stimulation, ascorbic acid is released from liposomes and reduce IONA to release abundant Fe 2+ . Moreover, IRE enhances tumor cell membrane permeability, thus facilitating efficient cytosolic Fe 2+ accumulation for effective tumor ferroptosis. Notably, the Fe 2+ release of EFN after IRE can be readily monitored by magnetic resonance imaging. Finally, IRE-triggered EFN demonstrates superior tumor growth inhibition, increased survival rates, and activation of immune cells, showing great potential for the development of next-generation spatiotemporally controlled ferroptotic therapies.