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Four biological barriers preventing activity of therapeutic oligonucleotide. (A) Endo-lysosomal entrapment. ON required escape from late endosome before subjected to lysosomal degradation. (B) Exonuclease cleavage. Initiate hydrolysis of phosphodiester backbone, which deteriorate ON. (C) Reticuloendothelial system. Digestion of ON by macrophage can terminate its activity. (D) Endothelium lining. Blockage of transverse ON from vascular lumen to interstitial fluid.
