Oxaliplatin-loaded natural killer cell-derived exosomes for a safe and efficient chemoimmunotherapy of colorectal cancer

In recent years, the limited biocompatibility and serious side effects of oxaliplatin (L-OHP) have restricted its clinical application. Exosomes are biologically active vesicles with a double membrane structure secreted by almost all living cells. They transport biomolecules (e.g., cytokines, proteins, neurotransmitters, and lipids) used for inter-cellular regulation and communication to target cells. Because of their excellent bio-compatibility, highly permeable and low-toxicity properties, exosomes are receiving widespread attention and importance as a drug delivery platform. In this study, we demonstrated the successful isolation of saucer-like Natural Killer cell exosomes (NK-Exosomes, NK-Exos) from NK cell cultures by density gradient centrifugation. The nano-drug delivery system (L-OHP-Exos) was successfully prepared using sonication. This nanomedicine delivery system based on exosomes effectively delivers chemotherapy drugs into tumor cells, inhibiting their growth. Moreover, it enhances the generation of reactive oxygen species (ROS) within tumor cells through the synergistic action of its Fas ligand (FasL) and oxaliplatin, subsequently inducing apoptosis. Following a series of rigorous in vivo experimental validations, we further confirmed the dual benefits of NK-Exos: their inherent growth inhibitory effects on tumors and their ability to markedly potentiate the antineoplastic activity of L-OHP in colorectal cancer therapy. Due to the limited solubility of oxaliplatin in phospholipid bilayers, encapsulation of oxaliplatin within L-OHP-Exos minimizes its binding to plasma proteins post-intravenous administration, thereby augmenting the sustained release and bioavailability of the drug. This nano-drug delivery system offers a novel approach for the treatment of colorectal cancer and holds promising potential for clinical application.