DNA-Programmed Stem Cell Niches via Orthogonal Extracellular Vesicle-Cell Communications

Extracellular vesicles (EVs) are natural carriers for intercellular transfer of bioactive molecules, which are harnessed for wide biomedical applications. However, a facile yet general approach to engineering interspecies EV-cell communications is still lacking. Here, the use of DNA to encode the heterogeneous interfaces of EVs and cells in a manner free of covalent or genetic modifications is reported, which enables orthogonal EV-cell interkingdom interactions in complex environments. Cholesterol-modified DNA strands and tetrahedral DNA frameworks are employed with complementary sequences to serve as artificial ligands and receptors docking on EVs and living cells, respectively, which can mediate specific yet efficient cellular internalization of EVs via Watson-Crick base pairing. It is shown that based on this system, human cells can adopt EVs derived from the mouse, watermelon, and Escherichia coli. By implementing several EV-cell circuits, it shows that this DNA-programmed system allows orthogonal EV-cell communications in complex environments. This study further demonstrates efficient delivery of EVs with bioactive contents derived from feeder cells toward monkey female germline stem cells (FGSCs), which enables self-renewal and stemness maintenance of the FGSCs without feeder cells. This system may provide a universal platform to customize intercellular exchanges of materials and signals across species and kingdoms.

Automated summary

This study presents a method for encoding the heterogeneous interfaces of extracellular vesicles (EVs) and cells using DNA, enabling interspecies EV-cell communications in complex environments. The use of cholesterol-modified DNA strands and tetrahedral DNA frameworks allows specific and efficient cellular internalization of EVs via base pairing. The system demonstrates orthogonal EV-cell communications and efficient delivery of bioactive contents derived from feeder cells to target cells.