Article

Co-delivery of shikonin and JQ1 inhibits triple-negative breast tumor progression and lung metastasis through inhibition of epithelial-mesenchymal transition and vasculogenic mimicry

Xing-yu Xu1,2, Dipika Ramdas Kalambhe1,2, Yue Yu1,2, Ling-xi Yu1,2, Zhi-wen Gu1,3, Xiao-ying Jin1,2, Hui-yuan Wang1, Yong-zhuo Huang1,2,4,5
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
4 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Zhongshan 528437, China
5 NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China
Correspondence to: Hui-yuan Wang: wanghuiyuan@simm.ac.cn, Yong-zhuo Huang: yzhuang@simm.ac.cn,
DOI: 10.1038/s41401-025-01605-8
Received: 7 April 2025
Accepted: 2 June 2025
Advance online: 14 July 2025

Abstract

Triple-negative breast cancer (TNBC) is highly prone to lung metastasis, primarily driven by epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM). Therefore, inhibiting EMT and VM represents a promising therapeutic strategy for TNBC. The immunosuppressive tumor microenvironment contributes substantially to poor treatment outcomes, with M2-type macrophages secreting excessive levels of TGF-β that promote both EMT and VM. In this study, we proposed a combination therapy strategy involving shikonin (SHK) and JQ1 delivered via a mesoporous polydopamine-based Pickering emulsion (termed MPDA@PE). This formulation significantly suppressed tumor growth and lung metastasis by inducing apoptosis in TNBC and inhibiting TGF-β-induced EMT and VM. Furthermore, MPDA@PE can be incorporated into a thermosensitive hydrogel for application in the prevention of TNBC recurrence and lung metastasis following surgical resection. These findings highlight a potential therapeutic approach for effective TNBC treatment.
Keywords: shikonin; JQ1; vasculogenic mimicry; epithelial-mesenchymal transition; mesoporous polydopamine nanoparticle; pickering emulsion

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