Precise co-delivery of drug and cytotoxic exosomes using a biomimetic nanorobot for glioma regression and recurrence prevention

Background: An increasing number of research studies have demonstrated the superiority of NK cells in clinical applications for cancer therapy. For a long time, the brain was considered as restricted area for immune cells because of the BBB, making the efficacy of NK cell-based immunotherapy on glioma is still insufficient. Therefore, a strategy to overcome the therapeutic bottlenecks of NK cell therapy for brain disease are urgently needed. In this study, we designed a biomimetic nanorobot termed “DTX@aNK Exos-NM” for enhancing the targeting ability and antitumor capacity. DTX@aNK Exos-NM was predesigned to have enhanced BBB penetration characterization and precise residual tumor targeting ability for delivery of both chemotherapeutic drugs and cytotoxic NK cell exosomes. Results: The biomimetic nanorobot was successfully established with both NK cell-liked and neutrophil-liked properties, as well as high loading efficiency and encapsulation efficiency of cytotoxic exosomes and chemotherapy drug. The transwell BBB model and C6-Luc glioma model in vivo study showed that DTX@aNK Exos-NM could penetrate the BBB and migrate to the residual tumor area efficiently in response to the inflammatory factors and Hsp70. In addition, DTX@aNK Exos-NM could effectively inhibit tumor proliferation and prolong survival time in a glioma mouse model. Conclusion: Our results indicate that the the well-designed DTX@aNK Exos-NM not only enhances the antitumor effect of NK cells but also efficiently promoting cellular uptake of cytotoxic exosomes and DTX by endothelial cells and tumor cells. The co-delivery of chemotherapeutic drugs and cytotoxic exosomes could slow the recurrence of residual tumor growth and significantly improves survival. This personalized both drugs and exosomes delivery platform responsive to post-radiotherapy microenvironment may provide a new opportunity for cancer treatment.