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Ovarian cancer stem cells (OCSCs) that are a subpopulation within bulk tumor survive chemotherapy and conduce to chemo-resistance and tumor relapse. However, conventional gene delivery is unsuitable for the on-demand content release, which limits OCSCs therapeutic utility. Here, we reported ultrasound-targeted microbubble destruction (UTMD)-triggerable poly(ethylene glycol)-disulfide bond-polyethylenimine loaded microbubble (PSP@MB). Taking advantage of glutathione (GSH) responsiveness, ultrasound triggering and spatiotemporally controlled release manner, PSP@MB is expected to realize local gene delivery for OCSCs treatment. But the biophysical mechanisms of gene delivery via PSP@MB and ultrasound remain unknown. The aim of this study is to determine the potential of gene delivery to OCSCs via ultrasonic synergistic biophysical effects and GSH-sensitive PSP@MB. The GSH-sensitive disulfide bond cleavable properties of PSP@MB were confirmed by 1H NMR spectra and infrared spectroscopy. The biophysical mechanisms between PSP@MB and cells were confirmed by scanning electron microscopy (SEM) and confocal laser scanning microscope (CLSM) to optimize the ultrasonic gene delivery system. The gene transfection via ultrasound and PSP@MB was closely related to the biophysical mechanisms (sonoporation, enhanced-endocytosis, sonoprinting, and endosomal escape). Ultrasound combined with PSP@MB successfully delivered aldehyde dehydrogenase 1 (ALDH1) short hairpin RNA (shRNA) plasmid to OCSCs and promoted apoptosis of OCSCs. The gene transfection rate and apoptosis rate were (18.41 ± 2.41)% and (32.62 ± 2.36)% analyzed by flow cytometry separately. This study showed that ultrasound triggering and GSH responsive PSP@MB might provide a novel strategy for OCSCs treatment via sonoporation and enhanced-endocytosis. [ABSTRACT FROM AUTHOR]