A versatile platform for chemical engineering of exosomes empowered by ADP-ribosyl cyclases

Cell-secreted exosomes have been emerging as an increasingly attractive form of nanomaterials for biomedical research. Various approaches have been established to genetically modify exosomes with proteins of interest for new and/or improved functions. However, equipping exosomes with diverse non-protein biomolecules remains largely dependent on random chemical conjugation or membrane insertion, hindering the application potential of exosomes. Herein, we develop a technology for site-specific functionalization of exosome with different synthetic groups by exploiting surface-expressed CD38, an ADP-ribosyl cyclase, and its covalent inhibitor derived from nicotinamide adenine dinucleotide (NAD⁺). The designed ADP-ribosyl cyclase-enabled exosomes (ARC Exos) carrying conjugated fluorescent imaging probes, small-molecule ligands, cytotoxic payloads, and bone-targeting agents are demonstrated with in vitro and/or in vivo activities and specificities. This ARC Exos-based platform provides a general approach with great versatility for chemically reprogramming exosomes.