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

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 Fe²⁺, face challenges associated with limited cytosolic Fe²⁺ 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 Fe²⁺. Moreover, IRE enhances tumor cell membrane permeability, thus facilitating efficient cytosolic Fe²⁺ accumulation for effective tumor ferroptosis. Notably, the Fe²⁺ 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.