Engineering natural killer cell-derived extracellular vesicles for disease therapy

As pivotal effector cells of the innate immune system, natural killer (NK) cells play indispensable roles in tumor immunosurveillance and the regulation of various chronic diseases. Despite their therapeutic potential, adoptive NK cell therapies are hindered by limited in vivo persistence and suboptimal tumor infiltration, thereby substantially restricting their clinical efficacy. Recently, NK cell-derived extracellular vesicles (NK-EVs) have attracted considerable attention as a cell-free strategy. They inherit the cytotoxic components of parental NK cells while possessing high biocompatibility, excellent stability, and significant tumor-penetrating capacity. NK-EVs have been shown to exert anticancer, immunoregulatory, anti-inflammatory, and anti-infective functions, contributing to therapeutic effects in both cancers and certain non-neoplastic diseases. As NK-EVs mirror the metabolic state of their parent cells and circulate systemically, they hold considerable promise as diagnostic biomarkers. Furthermore, NK-EVs can be engineered or modified to optimize their applications, notably in cancer therapy. This review provides a comprehensive overview of recent advances in NK-EVs, focusing on their therapeutic effects in cancer and non-neoplastic diseases, their role as biomarkers, and the development of engineered NK-EVs for cancer therapy, while also discussing key challenges and future perspectives for clinical translation.