The cell seretome is diverse and contains extracellular secreted vesicles (EVs) as well as non-vesicular extracellular nanoparticles (NVEPs) called exomeres and supermeres, all of which carry different kinds of cell signaling cargos. We have developed new techniques to purify exomeres and supermeres by ultracentrifugation (UC) and by fast protein liquid chromatography (FPLC) from cell conditioned media and from blood plasma. We utilized a proteomics approach to compare UC and FPLC methods with standard UC and density gradient methods of isolating EVs and new methods of isolating NVEPs. We acquired LC-MS/MS data from conditioned media using standard 2D plastic and hollow fiber 3D bioreactor production from a CRC cell line, DiFi, using all these methods and growth culture conditions.