Extracellular Vesicles as Drug Delivery System for the Treatment of Neurodegenerative Disorders: Optimization of the Cell Source

Extracellular vesicles (EVs) represent a next generation drug delivery system that combines nanoparticle size with extraordinary ability to cross biological barriers, reduced immunogenicity, and low offsite toxicity profiles. A successful application of this natural way of delivering biological compounds requires deep understanding EVs intrinsic properties inherited from their parent cells. Herein, we evaluated EVs released by cells of different origin, with respect to drug delivery to the brain for treatment of neurodegenerative disorders. The morphology, size, and zeta potential of EVs secreted by primary macrophages (mEVs), neurons (nEVs), and astrocytes (aEVs) were examined by nanoparticle NTA, DLS, cryoTEM, and AFM. Spherical nanoparticles with average size 110-130 nm and zeta potential around -20 mV were identified for all EVs types. mEVs showed the highest levels of tetraspanins and integrins compared to nEVs and aEVs, suggesting superior adhesion and targeting to the inflamed tissues by mEVs. Strikingly, aEVs were preferentially taken up by neuronal cells <em>in vitro</em>, followed by mEVs and nEVs. Nevertheless, the brain accumulation levels of mEVs in a transgenic mouse model of Parkinson's disease were significantly higher than those of nEVs or aEVs. Therefore, mEVs were suggested as the most promising nanocarrier system for drug delivery to the brain.