DNA‐Programmed Stem Cell Niches via Orthogonal Extracellular Vesicle–Cell Communications

Abstract 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.