Exosome-like nanovesicles from efficient sequential Co-delivery of anti-PDL1 and miR-375 for enhancing gene/immune therapy.

[BACKGROUND] Esophageal cancer is one of the common malignant tumors of digestive system. Despite many advances in the treatment of esophageal cancer, many challenges remain. As an endogenous extracellular vesicle, exosomes are increasingly presenting their immense potential in drug delivery. However, it remains a bottleneck to obtain a large quantity of uniform, stable, and multi-component controllable exosomes with low cost and time.

[METHODS] A novel targeted drug delivery system based on exosome-like nanovesicles has been developed using the natural Marine single-celled salt (DENV) to conjugate c (RGDyK) peptide on its surface to achieve targeted drug delivery to esophageal cancer cells. In addition, miR-375 was loaded into cRGD-DENV by electroporation and aPD-L1 was coupled to its surface by matrix metalloproteinase-2 (MMP-2). Characterizations were performed to confirm the successful preparation of engineered exosomes. The effects of engineered exosomes on tumor cell viability, migration, invasion and apoptosis were examined and the effects of engineered exosomes on esophageal cancer cells were further verified .

[RESULTS] The engineered DENV delivery system was prepared and characterized. It exhibited a uniform particle diameter (approximately 150 nm) with sustained release features in the presence of MMP-2/9. Importantly, the cRGD-DENV was effective, promoted selective delivery of cargoes to the tumor site, and reduced nonspecific uptake of the DENV cargoes, significantly inhibiting tumor growth . results showed that cRGD-DENV-aPDL1/miR375 significantly inhibited tumor growth and affected the proliferation, migration and invasion of esophageal cancer cells by regulating YWHAZ.

[CONCLUSIONS] The potential of exosome-like nanovesicle carrier delivery system in cancer therapy and can provide a very promising platform for the rapid and large-scale generation of functionalized exosome-like nanovesicles.