ISL@mTOMV nanoparticles: a promising approach for VM-targeted therapy in breast cancer.

Vasculogenic mimicry (VM) in breast cancer is recognized as an important non-endothelium-dependent vascular mechanism that promotes tumor invasiveness, survival, and metastatic potential; however, effective and specific intervention strategies remain limited. In this study, we innovatively constructed a nanodelivery system based on hybrid membranes derived from bacterial outer membrane vesicles and breast cancer cell membranes, termed mTOMV, and loaded it with the natural flavonoid isoliquiritigenin (ISL) to enhance targeted antitumor activity. ISL@mTOMV nanoparticles exhibited a uniform spherical morphology, favorable stability, and good biocompatibility. In vitro experiments demonstrated that ISL@mTOMV significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 and MCF-7 breast cancer cells, while promoting tumor cell apoptosis. Mechanistically, ISL@mTOMV markedly reduced the expression of ACLY, H3K27ac, and SMAD5 and suppressed the activity of the TGF-β/SMAD signaling pathway. In vivo experiments further confirmed that ISL@mTOMV inhibited ACLY-mediated H3K27 acetylation, attenuated SMAD5 transcriptional activation, and blocked TGF-β/SMAD signaling, thereby significantly suppressing VM formation in breast cancer. Collectively, this study proposes a highly biocompatible and tumor-targeted nanotherapeutic strategy, providing a new technical approach and potential translational value for VM intervention in breast cancer.