2. Academic Validation
  3. Exosomal delivery of AZD5582 to overcome TRAIL resistance as an optimal therapy against triple-negative breast cancer

Exosomal delivery of AZD5582 to overcome TRAIL resistance as an optimal therapy against triple-negative breast cancer

  • Acta Histochem. 2025 May 24;127(3):152270. doi: 10.1016/j.acthis.2025.152270.
Wanting Zhang 1,  Quanjiang Li 2,  Rui Tian 3,  Zhujie Deng 4,  Ronghui Sun 5,  Xiubin Kuang 6,  Jun Peng 7,  Bin Xie 8,  Chen Huang 9,  Zhengqiang Yuan 10
Affiliations

Affiliations

  • 1 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112212024@mail2.gdut.edu.cn.
  • 2 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112212044@mail2.gdut.edu.cn.
  • 3 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112212035@mail2.gdut.edu.cn.
  • 4 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112212059@mail2.gdut.edu.cn.
  • 5 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112312086@mail2.gdut.edu.cn.
  • 6 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112312088@mail2.gdut.edu.cn.
  • 7 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112412020@mail2.gdut.edu.cn.
  • 8 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: 2112412030@mail2.gdut.edu.cn.
  • 9 The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou 511400, PR China. Electronic address: huangchen@pyhospital.com.cn.
  • 10 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: yuanzq@gdut.edu.cn.
PMID: 40413911 DOI: 10.1016/j.acthis.2025.152270
Abstract

Triple-negative breast Cancer (TNBC) is a highly aggressive subtype of breast Cancer that lacks effective targeted therapies mainly due to drug resistance. Therefore, there is an urgent need to develop highly effective therapeutic strategies for TNBC. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces Apoptosis in transformed and cancerous cells, indicating its potential for anti-cancer therapy. Unfortunately, the clinical trials of recombinant TRAIL (rTRAIL) had actually failed due to the very common TRAIL resistance in cancers. Exosomal delivery of TRAIL (EV-T) has been shown to greatly improve the cytotoxicity of TRAIL. Moreover, the TRAIL resistance was closely correlated with the upregulation of inhibitors of Apoptosis proteins (IAPs) in Cancer cells. As a potent antagonist of IAPs, AZD5582 (AZD) was previously shown to drastically sensitize TRAIL response. Herein, we hypothesize that AZD may be loaded into EV-T for co-delivery of AZD and TRAIL to make a synergistic combination Anticancer therapy against TNBC. First, TRAIL-expressing mesenchymal stem cells (MSCs) were used to prepare EV-Ts. Then, AZD was loaded into EV-T by ultrasound to prepare the composite nanodrug AZD@EV-T. EV encapsulation significantly improved AZD stability and cellular delivery efficiency, leading to the synergistically augmented cytotoxicity and Apoptosis induction in both breast and kidney Cancer cell lines, whilst sparing the normal MSCs. The potential mechanisms underlying the synergism appeared to be associated with the concomitant upregulation of Death Receptor 5 (DR5) and expressional suppression of various anti-apoptotic factors. Importantly, the AZD@EV-T therapy triggered strikingly enhanced growth inhibition and Apoptosis in the subcutaneously established BT549 xenograft tumors, consequently leading to the complete tumor regression. It also demonstrated significant potential for treating kidney Cancer in A498 kidney tumor organoids. Together, AZD@EV-T effectively overcomes TRAIL resistance and may represent a highly effective and innovative Anticancer therapy for both TNBC and kidney cancers.

Keywords

AZD5582; Composite nanodrug; Drug resistance; TNBC; TRAIL.

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