Mesenchymal stem cell-derived exosomes (MSC-Exos), noted for their minimal immunogenicity and robust immunomodulatory potential, have emerged as key regulators of immune cell fate. Nevertheless, a comprehensive understanding of their global impact on human NK cell proliferation and effector function remains elusive. In this study, we employed a standardized ex vivo expansion and exosome-priming system to systematically evaluate the regulatory effects of MSC-Exos on peripheral blood-derived NK cells via flow cytometry, cytotoxicity assays, single-cell transcriptomics, and proteomic profiling. Proteomic profiling identified an enrichment of FcγR-related signaling components within MSC-Exos, suggesting a potential role in enhancing antibody-dependent cellular cytotoxicity (ADCC).Collectively, our findings demonstrate that MSC-Exos bolster NK cell expansion and effector maturation through coordinated immuno-metabolic reprogramming, offering a strategic approach to enhancing the therapeutic efficacy of NK cell-based immunotherapies.