Pretreating Mesenchymal Stem Cells with Cancer Conditioned-Media or Proinflammatory Cytokines Changes the Tumor and Immune Targeting by Nanoghosts Derived from these Cells.

Abstract

Nanoghosts (NGs) are nanovesicles reconstructed from the cytoplasmic membranes of mesenchymal stem cells (MSCs). By retaining MSC membranes, the NGs retain the ability of these cells to home in on multiple tumors, laying the foundations, thereby, for the development of a targeted drug delivery platform. The susceptibility of MSCs to functional changes, following their exposure to cytokines or cancer-derived conditioned-media (CM), presents the opportunity to modify the NGs by conditioning their source cells. This opportunity is investigated by comparing the membrane protein composition and the tumor uptake of NGs derived from naïve MSCs (N-NG) against conditioned NGs made from MSCs pre-treated with conditioned-media (CM-NG) or with a mix of the proinflammatory cytokines TNF-α and IL-1β (Cyto-NG). CM-NGs are found to be more targeted towards immune cells than Cyto- or N-NGs, while Cyto-NGs are the most tumor-targeted ones, with similar immune-targeting capacity as N-NGs but with a higher affinity towards endothelial cells. Proteomic variations were wider in the CM-NGs, with exceptionally higher levels of ICAM-1 compared to N- and Cyto-NGs. From a translational point of view, the data show that the tumor-targeting ability of the NGs, and possibly that of other MSC-derived extracellular vesicles, can be enhanced by simple conditioning of their source cells.