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Extracellular vesicles (EVs) are future promising therapeutics, but their instability in vivo after administration remains an important barrier to their further development. Many groups evaluated EV surface modification strategies to add a targeting group with the aim of controlling EV biodistribution. Conversely, fewer groups focused on their stabilization to obtain "stealth" allogenic EVs. Modulating their stabilization and biodistribution is an essential prerequisite for their development as nano-therapeutics. Here, we explored polyoxazolines with lipid anchors association to the EV membrane (POxylation as an alternative to PEGylation) to stabilize EVs in plasma and control their biodistribution, while preserving their native properties. We found that this modification maintained and seemed to potentiate the immunomodulatory properties of EVs derived from mesenchymal stem/stromal cells (MSC). Using a radiolabeling protocol to track EVs at a therapeutically relevant concentration in vivo , we demonstrated that POxylation is a promising option to stabilize EVs in plasma because it increased EV half-life by 6 fold at 6 h post-injection. Moreover, EV accumulation in tumors was higher after POxylation than after PEGylation. [Display omitted] • Preservation of mouse MSC-EV native immunomodulatory properties after POxylation. • Radiolabeling protocol allowed EV detection after intravenous administration of 1.108 EVs/mouse until 24h. • POxylated EVs showed enhanced plasma stabilization after intravenous administration in mice. • Higher accumulation in PANC-1 cell tumors of POxylated EVs than PEGylated EVs. [ABSTRACT FROM AUTHOR]