Designer biomimetic vectors are genetically engineered biomacromolecules that are designed to mimic viral characteristics in order to overcome the cellular barriers associated with the targeted gene transfer. The vector in this study was genetically engineered to contain at precise locations: a) four tandem repeating units of N-terminal domain of histone H2A to condense DNA into stable nanosize particles suitable for cellular uptake, b) a model targeting motif to target HER2 and enhance internalization of nanoparticles, and c) a pH-responsive synthetic fusogenic peptide to disrupt endosome membranes and promote escape of the nanoparticles into the cytosol. The results demonstrate that a fully functional, multi-domain, designer vector can be engineered to target cells with high specificity, overcome the biological barriers associated with targeted gene transfer, and mediate efficient gene transfer.
A biomimetic vector was genetically engineered to contain at precise locations (a) an adenovirus mu peptide to condense pDNA into nanosize particles, (b) a synthetic cyclic peptide to target breast cancer cells and enhance internalization of nanoparticles, (c) a pH-responsive synthetic fusogenic peptide to disrupt endosome membranes and facilitate escape of the nanoparticles into the cytosol, and (d) a nuclear localization signal from human immunodeficiency virus for microtubule mediated transfer of genetic material to the nucleus. The vector was characterized using physicochemical and biological assays to demonstrate the functionality of each motif in the vector backbone. The results demonstrated that the vector is able to condense plasmid DNA into nanosize particles (<100 nm), protect pDNA from serum endonucleases, target ZR-75-1 breast cancer cells and internalize, efficiently disrupt endosome membranes, exploit microtubules to reach nucleus and mediate gene expression. The therapeutic potential of the vector was evaluated by complexing with plasmid DNA encoding TRAIL (pTRAIL) and transfecting ZR-75-1 cells. The results demonstrated that up to 62% of the ZR-75-1 breast cancer cells can be killed after administration of pTRAIL in complex with the vector.
With the emergence of new technologies such as recombinant bio-inspired vectors, it may not take long before non-viral vectors are observed that are not just safe and tissue-specific, but even more efficient than viral vectors.
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