An electro-ferroptotic nanoammunition enables image-guided, spatiotemporally controlled cancer ferroptosis induction via irreversible electroporation
Jun‐Hyeok Han, Hee Seung Seo, Jiyoung Lee, Zheng Chen, Qiyue Wang, Yun Young Lee, Na Kyeong Lee, Jeon Min Kang, Song Hee Kim, Hwichan Hong, Jung‐Hoon Park, Yuanzhe Piao, Fangyuan Li, Kun Na, Chun Gwon Park, Wooram Park, Daishun Ling
Abstract
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.