Developing strategies to induce apoptosis in cancer cells through its molecular players, such as Bcl-2, is of great importance in cancer treatment. Triggering apoptosis simultaneously both by extrinsic and intrinsic pathways can reverse apoptosis evasion in the cancer cells. NK-cell exosomes (NKExos) contribute to cancer treatment by interacting with tumor and immune cells, and inducing tumor cell apoptosis by the extrinsic pathway. In this study, NKExos from NK-92MI cells loaded with siBcl-2 by lentivirally transducing the cells with Bcl-2 siRNA, were intratumorally administered twice a week to the xenograft breast cancer model in athymic mice. The most significant reduction in tumor diameter was detected in the group in which siBcl-2 loaded NKExos (65%) were applied. Immunohistochemical studies have shown that Bcl-2 protein in the breast tumor tissues were decreased upon exosomes administration.  When degree of apoptosis in the tumor tissue was studied by TUNEL assay, it was observed that apoptosis was increased significantly in the group given exosomes loaded with Bcl-2 siRNA. Caspase 8, 9 and 10 mRNA expressions were found to be significantly increased in tumors treated in the siBcl-2 containing NKExo. It was determined that administering intravenously NKExos accumulated most in the liver and reached the tumor tissue. In our study, the antitumor effects of NK exosomes were combined with the use of exosomes as a gene carrier system and were successfully used for Bcl-2-based gene therapy in breast cancer. This research has been supported by The Scientific and Technological Research Council of Turkey, TÜBİTAK-1001 (217S455)