Glutathione-scavenging natural-derived ferroptotic nano-amplifiers strengthen tumor therapy through aggravating iron overload and lipid peroxidation

Ruie Chen; Liewei Wen; Feng Guo; Jiawen He; Ka Hong Wong; Meiwan Chen

doi:10.1016/j.jconrel.2025.01.026

Glutathione-scavenging natural-derived ferroptotic nano-amplifiers strengthen tumor therapy through aggravating iron overload and lipid peroxidation

J Control Release. 2025 Jan 20:S0168-3659(25)00028-8. doi: 10.1016/j.jconrel.2025.01.026. Online ahead of print.

Authors

Ruie Chen¹, Liewei Wen², Feng Guo¹, Jiawen He³, Ka Hong Wong¹, Meiwan Chen⁴

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China; Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, Guangdong 519000, China. Electronic address: wenliewei@ext.jnu.edu.cn.
³ Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, Guangdong 519000, China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China. Electronic address: mwchen@um.edu.mo.

PMID: 39842724
DOI: 10.1016/j.jconrel.2025.01.026

Abstract

Nanomedicine-driven ferroptosis has emerged as a promising tumor treatment strategy through delivering exogenous iron and aggravating the lethal accumulation of lipid peroxides (LPO). However, the compensatory mechanisms of ferroptosis defense systems in cancer cells compromise the therapeutic efficacy and lead to potential side effects. Herein, a highly effective ferroptotic nano-amplifier is designed to synergistically promote ferroptosis via increasing intracellular labile iron, exacerbating lipid peroxidation and overcoming the defense system. Briefly, a natural-derived amphiphilic polymer composing of chondroitin sulfate (CS), arachidonic acid (AA) and a redox-sensitive linker, cystamine (CYS) is constructed to self-assemble as a GSH-responsive nanodrug delivery system for loading bioactive ingredient Polyphyllin I (PPI) and ferric ion (Fe³⁺). This nanodrug (CSAA/Fe@PPI) can scavenge the aberrant intracellular GSH via CYS linker, accompanied with the degradation of CSAA/Fe@PPI and the release of PPI, AA and Fe³⁺. On one hand, the intracellular labile iron level is significantly elevated due to the exogenous delivery of Fe³⁺ and PPI-induced ferritinophagy. On the other hand, ROS burst and the supplement of AA initiate and propagate the lipid peroxidation chain reaction. Meanwhile, the depletion of intracellular GSH suppresses the GPX4 activity, further strengthening the lethal accumulation of LPO. Consequently, the ferroptotic antitumor efficacy is remarkably improved by systemically aggravating iron overload and lipid peroxidation. Therefore, our study presents an effective strategy to improve ferroptosis-based anti-cancer treatment through multiple intervention routes.

Keywords: Autophagy; Ferroptosis; Iron overload; Natural-derived nano-delivery system; Polyphyllin I.