Non-planar perylene diimides dual-targeting mitochondrial membrane potential and mitochondrial DNA transcription for an-titumor Therapy

Mitochondrial DNA (mtDNA) transcription is an emerging target in cancer therapy. While enzyme-targeted inhibitors such as IMT1B block POLRMT, their organelle specificity remains unclear. Here, we report a distinct strategy using non-planar perylene diimide derivatives (PDIs). The fluorescent lead compound PDIC-BL combines mitochondrial membrane potential ({Delta}{Psi}m) dependent accumulation (validated in cells and isolated mitochondria), and with direct intercalation into mtDNA (Kd = 32 M), as demonstrated by single-molecule stretching assays. This dual-targeting mechanism leads to selective inhibition of mitochondrial transcription, ROS generation and triggers apoptosis. PDIC-BL exhibits superior antitumor efficacy in breast cancer cell lines (MCF-7, MDA-MB-231) and significantly supresses tumor growth in vivo, with good tolerability in cancer xenograft model in nude mice. This work not only elucidates the structure-activity relationship of non-planar PDIs, but also offers a generalizable strategy for developing organelle-selective DNA binding therapeutics.