Red Blood Cell-derived Extracellular Vesicles as biomaterials: the opportunity of freezing-induced accelerated aging
Lucia Paolini,
Miriam Romano,
Valentina Mangolini,
Selene Tassoni,
Shuhan Jiang,
Elena Laura Mazzoldi,
Angelo Musicò,
Andrea Zendrini,
Anna Kashkanova, et al.
Biomaterials Science
14
122-139
(2026)
| Journal
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Red blood cell-derived extracellular vesicles (RBC-EVs) are emerging as promising biomaterials for next-generation drug delivery, owing to their intrinsic biocompatibility, immune evasion properties, and minimal oncogenic risk. However, their broader application is currently limited by unresolved challenges related to heterogeneity, reproducibility, and long-term storage stability. By combining discontinuous sucrose density gradient separation with high-resolution interferometric nanoparticle tracking analysis, we identified a sharp bimodal size distribution of the vesicles in freshly prepared samples. We then tracked how long-term storage at −80 °C drove its conversion into a monomodal distribution. To reproduce these conditions in a shorter time frame, we developed an “accelerated-ageing” protocol based on freeze–thaw cycles that generates RBC-EV samples with homogeneous density, size distribution, and biological activity, effectively replicating the properties of preparations stored for six months at −80 °C. This new vesicle population results stable and retains membrane integrity and cellular internalization capacity, as confirmed by surface-associated enzymatic activity assays and uptake tests in cancer cell lines. These results suggest that freezing-induced “accelerated ageing” represents an effective method for the optimization and standardization of RBC-EVs as building blocks for biomaterial and bioengineering applications.
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