Breast cancer has now surpassed lung cancer as the leading cause of cancer-related deaths among women worldwide. Given the urgent need for more effective treatment, extracellular vesicles (EVs) have gained attention as versatile and promising drug delivery systems. Derived from a variety of cell types, EVs can be loaded with therapeutic cargo or engineered to present specific surface ligands and receptors. These EV modifications enable them to overcome many limitations associated with conventional therapies. In this review, we highlight current methodologies for loading small molecule drugs, RNA-based therapeutics, and proteins into EVs through both pre-isolation (endogenous) and post-isolation (exogenous) methods. We further discuss recent advances in EV surface engineering strategies aimed at improving tumor-specific targeting and immunotherapeutic efficacy in breast cancer.

Triple-negative breast cancer (TNBC) remains a significant challenge in oncology, contributing to a significant portion of cancer-related deaths among women. Current therapeutic options, including chemotherapy, surgery, radiation, and hormonal targeting therapies, exhibit limited efficacy, necessitating the exploration of innovative treatment modalities. The emergence of drug resistance and the persistence of cancer stem cells (CSCs) further emphasize the urgent need for novel therapeutic strategies. In this context, natural killer cell-derived extracellular vesicles (NK-EVs) have emerged as a promising cell-free therapeutic approach that exhibits high tumor infiltration and cytotoxicity against cancer cells and CSCs. This study aims to investigate the efficacy of NK-EVs as a therapeutic strategy for TNBC using various clinically relevant models, including patient-derived xenografts. Pathway analysis suggests strong activation of apoptosis via canonical caspase activation, as well as necrosis, thereby confirming the important cytotoxic effect of NK-EVs. Interestingly, NK-EVs were also found to suppress TNBC CSCs by disrupting their functionality and viability, and NK-EV treatment increased the expression of apoptosis markers in both CSCs and non-CSCs. By elucidating the therapeutic efficacy and translational potential of NK-EV-based interventions in TNBC, these findings offer critical insights for the development of future immunotherapeutic strategies against this aggressive subtype of breast cancer.