Delivery of High Mobility Group Box-1 siRNA using brain-targeting exosomes for ischemic stroke therapy.


Ischemic strokes are caused by decreased blood flow into the brain, due to narrowed cerebral arteries. In the ischemic brain, high-mobility group box 1 (HMGB1) is released into extracellular spaces and induces inflammatory reactions. In this study, researchers from the Korea University delivered HMGB1 small interfering RNA (siRNA) into ischemic brains by intravenous administration using rabies virus glycoprotein (RVG) peptide-decorated exosomes. A fusion protein of RVG and Lamp2b was expressed in 293T cells. Since Lamp2b is an exosome membrane-integral protein, RVG-Lamp2b is integrated into the exosomes, producing RVG-decorated exosomes (RVG-Exo). HMGB1-siRNA was loaded into RVG-Exo and unmodified exosomes (Unmod-Exo) by electroporation. The exosomes were homogenous with a size of less than 50 nm and a negative surface charge. In vitro delivery assays showed that RVG-Exo showed higher efficiency to Neuro2A cells than Unmod-Exo. Also, HMGB1 levels were reduced more effectively by RVG-Exo/HMGB1-siRNA. In vivo delivery efficiency and therapeutic effects of RVG-Exo/HMGB1-siRNA were evaluated in a middle cerebral artery occlusion (MCAO) model. RVG-Exo/HMGB1-siRNA, Unmod-Exo/HMGB1-siRNA, and PEI25k/HMGB1-siRNA were administrated into the MCAO model intravenously through the tail vein. The results showed that HMGB1, tumor necrosis factor-α (TNF-α), and apoptosis levels in the brain were reduced in the RVG-Exo/HMGB1-siRNA group more efficiently than the other groups. In addition, the infarct size was decreased in the RVG-Exo/HMGB1 group more effectively than the other groups. These results suggest that RVG-Exo with HMGB1-siRNA may have potential as a therapeutic system for the treatment of ischemic strokes.

Kim M, Kim G, Hwang DW, Lee M. (2019) Delivery of High Mobility Group Box-1 siRNA Using Brain-Targeting Exosomes for Ischemic Stroke Therapy. J Biomed Nanotechnol 15(12):2401-2412. [abstract]

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