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    Therapeutic Silencing of BCL-2 Using NK Cell-Derived Exosomes as a Novel Therapeutic Approach in Breast Cancer
    (Mdpi, 2021) Kaban, Kuebra; Hinterleitner, Clemens; Zhou, Yanjun; Salva, Emine; Kantarci, Ayse Gulten; Salih, Helmut R.; Maerklin, Melanie
    Simple Summary Overexpression of the antiapoptotic protein BCL-2 is correlated with estrogen receptor (ER) expression in breast cancer and plays an important role for disease pathophysiology. Here, we conceptualized a novel treatment strategy by targeting ER+ breast cancer with NK cell-derived exosomes used as a carrier for BCL-2 targeted siRNAs. With this new approach, we successfully enhanced killing ability of NK cell derived exosomes by silencing of BCL-2 overexpression. Overexpression of the anti-apoptotic protein BCL-2 is frequently observed in multiple malignancies, including about 85% of patients with estrogen receptor positive (ER+) breast cancer. Besides being studied as a prognostic marker, BCL-2 is investigated as a therapeutic target in ER+ breast cancer. Here, we introduce a new exosome-based strategy to target BCL-2 using genetically modified natural killer (NK) cells. The NK cell line NK92MI was lentivirally transduced to express and load BCL-2 siRNAs (siBCL-2) into exosomes (NKExos) and then evaluated for its potential to treat ER+ breast cancer. Transfected NK92MI cells produced substantial levels of BCL-2 siRNAs, without substantially affecting NK cell viability or effector function and led to loading of siBCL-2 in NKExos. Remarkably, targeting BCL-2 via siBCL-2 NKExos led to enhanced intrinsic apoptosis in breast cancer cells, without affecting non-malignant cells. Together, our prototypical results for BCL-2 in breast cancer provide proof of concept for a novel strategy to utilize NKExos as a natural delivery vector for siRNA targeting of oncogenes.