Mesenchymal stem cell-derived extracellular vesicle therapy in breast cancer: A systematic review and meta-analysis of in vitro studies

Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutics for breast cancer due to their innate tumor tropism and molecular delivery capacity. This systematic review and meta-analysis evaluated the <i>in vitro</i> therapeutic potential and safety of MSC-EVs. A comprehensive search up to July 2025 identified 58 eligible studies. Quantitative data were extracted on cell viability, apoptosis, and migration, along with EV source, cargo, and engineering strategy. Random-effects meta-analyses showed that MSC-EV treatment significantly reduced cancer cell viability (standardized mean difference [SMD] = -4.79), inhibited migration (SMD = -4.70), and increased apoptosis (SMD = +4.16). Effects were consistent across major cell lines (MCF-7, MDA-MB-231, and 4T1) and MSC sources (bone marrow, adipose, and umbilical cord), despite moderate heterogeneity (I² = 50%-70%). Notably, unmodified bone marrow MSC-EVs carrying miR-23b were associated with dormancy induction <i>in vivo</i>, whereas engineered EVs loaded with therapeutic miRNAs or drugs and modified with targeting ligands demonstrated improved specificity and efficacy. Precision engineering of MSC-EVs can enhance antitumor activity but requires stringent cargo control to avoid dormancy risks. Only <i>in vitro</i> data were quantitatively analyzed, while <i>in vivo</i> findings were discussed for mechanistic context, providing a methodological foundation for future translational research.