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Summary: Exomeres are a recently discovered type of extracellular nanoparticle with no known biological function. Herein, we describe a simple ultracentrifugation-based method for separation of exomeres from exosomes. Exomeres are enriched in Argonaute 1–3 and amyloid precursor protein. We identify distinct functions of exomeres mediated by two of their cargo, the β-galactoside α2,6-sialyltransferase 1 (ST6Gal-I) that α2,6- sialylates N-glycans, and the EGFR ligand, amphiregulin (AREG). Functional ST6Gal-I in exomeres can be transferred to cells, resulting in hypersialylation of recipient cell-surface proteins including β1-integrin. AREG-containing exomeres elicit prolonged EGFR and downstream signaling in recipient cells, modulate EGFR trafficking in normal intestinal organoids, and dramatically enhance the growth of colonic tumor organoids. This study provides a simplified method of exomere isolation and demonstrates that exomeres contain and can transfer functional cargo. These findings underscore the heterogeneity of nanoparticles and should accelerate advances in determining the composition and biological functions of exomeres. : Exomeres are nanoparticles recently identified by asymmetric flow field-flow fractionation. Zhang et al. develop a simplified method for exomere isolation and confirm that exomeres have unique protein and lipid profiles. They show that two exomere cargos, ST6Gal-I and AREG, are biologically active in recipient cells. Keywords: exomeres, exosomes, extracellular vesicles, ST6Gal-I, amphiregulin, organoids, EGFR, Argonautes, fluorescence-activated vesicle sorting, β1-integrin