biostudies-literatureZhang LU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)NIBIB NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)U.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHSNIGMS NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering932https://www.ebi.ac.uk/biostudies/studies/S-EPMC12830964biostudies-literatureUnknown17(1)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 fluoreNature communicationsA versatile platform for chemical engineering of exosomes empowered by ADP-ribosyl cyclases.PMC12830964P30 CA014089R01 CA276240R35 GM137901R35GM137901R01CA276240P30CA014089R01EB031830R01 EB031830Shen KKim SHHoang TOZhang ZCheng QZhang YSingireddi SZhang LSkorka TAnsari AJKao GDuan XfalseA 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 fluore2025-01-01T00:00:00Z2025 Dec2026-06-16T07:29:33.846Z2026-06-16T03:10:13.502ZS-EPMC128309644141947010.1038/s41467-025-67661-0