Surface-Engineered Natural Killer Cell-Derived Small Extracellular Vesicles Induce Potent Anti-Tumour Effects in Lung Cancer Cells

Abstract

Small extracellular vesicles (sEVs) derived from natural killer (NK) cells possess inherent anti-tumour activity and offer the advantages of cell-free therapy. In this study, we genetically engineered NK-sEVs to express interleukin 15 (IL15), an anti-tumour cytokine, and the monoclonal antibody cetuximab on their surface, creating a potent anti-tumour immunotherapy with enhanced tumour-targeting capabilities. These IL15- and cetuximab-tethered NK-sEVs (eEVs) were generated using lentivirus-based modification. eEVs selectively bound to EGFR+ cancer cells in vitro, confirming cetuximab-mediated targeting. Compared to control NK-sEVs, eEVs exhibited significantly enhanced cytotoxicity by directly inducing cancer cell death and promoting NK cell-mediated killing. In a lung cancer mouse model, eEVs selectively accumulated in tumours and exhibited significant anti-tumour efficacy. Notably, their administration, alone or in combination with anti-PD-1 antibody therapy, effectively suppressed tumour growth. Overall, our results indicate that genetically engineered NK-sEVs, equipped with IL15 and cetuximab, exhibit potent anti-tumour activity and tumour-targeting capabilities. These findings suggest that eEVs hold significant potential as a novel immunotherapeutic strategy for cancer treatment. © 2025 Elsevier B.V., All rights reserved.