Differential Effects of Mesenchymal Stem Cell- and Natural Killer Cell-Derived Extracellular Vesicles on Cisplatin Responsiveness in Endometrial Cancer Cells

Cisplatin (cis-diamminedichloroplatinum(II) [DDP]) is a key chemotherapeutic agent for advanced endometrial cancer; however, chemoresistance substantially limits its clinical benefit. Extracellular vesicles (EVs) mediate intercellular communication and influence tumour cell behaviour and therapeutic response. We investigated whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and natural killer cell-derived extracellular vesicles (NK-EVs) modulate cisplatin responsiveness in endometrial cancer cells (RL95-2 and HEC-1A). MSC-EVs and NK-EVs were isolated and characterised using nanoparticle tracking analysis, scanning electron microscopy, and EV marker profiling. MSC-EVs and NK-EVs reduced RL95-2 and HEC-1A cell viability in a dose-dependent manner, with MSC-EVs exhibiting substantial effects at lower particle concentrations. In a cisplatin-resistant HEC-1A (HEC-1A DDP-R) model, MSC-EVs were associated with greater reductions in cell viability under cisplatin treatment conditions, whereas NK-EVs showed comparatively modest effects. Mechanistic analyses demonstrated altered expression of apoptosis- and cell cycle–related proteins, including increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels and reduced cyclin A and cyclin D1 expression following MSC-EV treatment. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry demonstrated increased apoptotic cell populations after MSC-EV treatment, with MSC-EV + DDP co-treatment resulting in the highest apoptotic fraction in chemoresistant HEC-1A cells. Collectively, these findings indicate that MSC-EVs are associated with altered cellular responses to cisplatin in chemoresistant endometrial cancer cells, accompanied by changes in apoptosis-related protein expression, apoptotic cell populations, and cell-cycle regulators. Further investigation is required to determine their mechanistic role and therapeutic potential in overcoming chemoresistance.