Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy.
10.1016/j.apsb.2025.03.014
- Author:
Muhammad HAMZA
1
;
Shuai WANG
1
;
Hao WU
1
;
Jiayi SUN
1
;
Yang DU
1
;
Chuting ZENG
1
;
Yike LIU
1
;
Kun LI
1
;
Xili ZHU
2
;
Huiying LIU
3
;
Lin CHEN
1
;
Motao ZHU
1
Author Information
1. CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
2. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, China.
3. College of Pulmonary and Critical Care Medicine, the 8th Medical Centre, Chinese PLA General Hospital, Beijing 100039, China.
- Publication Type:Journal Article
- Keywords:
Akkermansia muciniphila;
Antioxidant protein 1 siRNA;
Breast cancer;
Cancer therapy;
Cuproptosis;
Elesclomol;
Outer membrane vesicle;
Tumor microenvironment
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2640-2654
- CountryChina
- Language:English
-
Abstract:
Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe-S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.
