Target-switchable nanoprobe based on BRD4 inhibition for induction and dynamic visualization of the mitochondrial apoptotic pathway

Ruijie Cao; Yijing Dang; Xinyue Liu; Qian Sun; Wen Zhang; Zhiai Xu

doi:10.1016/j.bios.2025.117179

Target-switchable nanoprobe based on BRD4 inhibition for induction and dynamic visualization of the mitochondrial apoptotic pathway

Biosens Bioelectron. 2025 Jan 16:273:117179. doi: 10.1016/j.bios.2025.117179. Online ahead of print.

Authors

Ruijie Cao¹, Yijing Dang², Xinyue Liu¹, Qian Sun¹, Wen Zhang³, Zhiai Xu⁴

Affiliations

¹ School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
² School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China. Electronic address: yjdang@chem.ecnu.edu.cn.
³ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, 200062, China. Electronic address: wzhang@chem.ecnu.edu.cn.
⁴ School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China. Electronic address: zaxu@chem.ecnu.edu.cn.

PMID: 39842059
DOI: 10.1016/j.bios.2025.117179

Abstract

The exploration of the mitochondrial apoptotic pathway in living cells is of great significance for achieving tumor diagnosis and treatment. However, visualization of the mitochondrial apoptotic pathway induced by specific proteins has rarely been reported. In this paper, we designed and synthesized a fluorescent probe Cy-JQ1 based on the bromodomain-containing protein 4 (BRD4) inhibition. Cy-JQ1 can affect mitochondrial electron chain transfer and reduce the mitochondrial membrane potential, effectively activating the Bcl-2/Bax/caspase-3 signaling pathway at a concentration of 500 nM and then triggering cell apoptosis. Due to its high specificity and excellent fluorescence properties, the switching of Cy-JQ1 from mitochondria to endoplasmic reticulum could be observed. The difference in fluorescence intensity along the perinuclear aggregates could be well defined as ΔXOR and used as a sensitive indicator of apoptosis. Upon conjugating with polyethylene glycol (PEG) containing disulfide bonds, the performance of the formed nanoprobe (Cy-JQ1-S-S-M) is further enhanced by improving pharmacokinetics and tumor-specific accumulation. This study provides a new analytical method for the dynamic visualization of mitochondria-induced apoptosis pathways triggered by specific proteins, as well as for the development of apoptosis-related target drugs.

Keywords: BRD4 inhibition; Dynamic visualization; Mitochondrial apoptotic pathway; Nanoprobe; Target-switchable; Tumor-targeting.