Exosome-based delivery of RNAi leads to breast cancer inhibition

Breast cancer is currently the most prevalent cancer in the world. It has been reported that hyperactivation and dysregulation of key pathways, such as PI3K/AKT/mTOR (PAM), contributes to the cell's tumorigenesis and resistance to existent therapies. Herein, we sought to uncover the potential of PAM downregulation in a panel of different breast cancer cell lines with different phenotypes, through PIK3CA silencing. This oncogene was targeted with a pre-designed small interfering RNA (siRNA) transfected onto PIK3CA wild-type MDA-MB-231cells and PIK3CA mutated MDA-MB-453cells. The results suggest that the siRNA efficiently targeted PIK3CA, triggering an efficient gene silencing and a decrease on cellular viability, as well as migration capacity. Moreover, exosome-like nanovesicles were successfully isolated, characterized and incorporated into the cells and served as excellent siRNA nanocarriers, promoting an incremented and faster onset. Altogether, the data gathered shows that the combination of the validated siRNA with these nanocarriers could be a promising targeted drug delivery system for an alternative breast cancer therapy.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit. Débora Ferreira is recipient of a fellowship supported by a doctoral advanced training (call NORTE-69-2015-15) funded by the European Social Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Débora Ferreira also acknowledges “Liga Portuguesa contra o cancro - Núcleo Regional do Norte (LPCC-530 NRN)“ for her fellowship. The authors thank Diana Vilas Boas (CEB/University of Minho) for confocal microscopy technical support.