Chapter fifteen - Multifunctional Envelope-Type Nano Device (MEND) for Organelle Targeting Via a Stepwise Membrane Fusion Process
Section snippets
Programmed Packaging Concept and Construction of R8-MEND
We recently developed a multifunctional envelope-type nano device (MEND) based on a new packaging concept called “Programmed Packaging” (Kogure et al., 2004, Kogure et al., 2008), in which various functional devices that control intracellular trafficking are packaged into single nanoparticles so as to permit them to function at the appropriate place and time. This concept consists of three components: (1) a program to overcome all barriers, (2) design of functional devices and their
Screening of Lipid Compositions for Their Ability to Fuse with Nuclear and Mitochondrial Membranes
Targeted delivery of an engineered gene or gene product to the nucleus or a mitochondrion is an essential first step toward the therapeutic restoration of a missing cellular function. The nuclear localization signal (NLS) peptide can be used to guide a protein to the nucleus (Yoneda et al., 1992). However, the same NLS does not function as such when attached to a pDNA (Nagasaki et al., 2003, Tanimoto et al., 2003): the positively charged NLS can be neutralized by the anionic pDNA, and it is
Construction of Tetra-Lamellar MEND (T-MEND)
As described above, the R8-MEND is capable of inducing macropinocytosis and can escape lysosomal degradation, leading to transfection activities as high as that for adenovirus in dividing cells (Khalil et al., 2007). However, in nondividing cells, the ultimate barrier, namely the nuclear membrane, must also be overcome. The R8-MEND cannot in corporate two kinds of envelopes with different compositions for different membrane fusions. To solve this problem, an innovative nanotechnology was
The nuclear membrane, an ultimate barrier to gene delivery to the nonmitotic cells
For a successful gene-delivery system, the nuclear membrane is the ultimate barrier that must be overcome. One of the typical results revealing its barrier function has been observed in the cell-to-cell variation in transgene expression. Flow cytometry analyses revealed that the percent of marker gene expression-positive cells to all cells analyzed was sharply enhanced when the cell cycle progressed through the M-phase (Tseng et al., 1999). Many investigators believe that the M-phase-specific
Mitochondrial Bioactive Molecule Delivery Using a Dual Function-MITO-Porter as a MEND for Mitochondrial Delivery
Mitochondrial dysfunction has recently been implicated in a variety of diseases (Chen and Chan, 2009, Kyriakouli et al., 2008, Reeve et al., 2008, Schapira, 2006, Tuppen et al., 2010, Wallace, 2005). Mutations and defects of mitochondrial DNA (mtDNA) are thought to be causes of mitochondrial diseases. Therefore, mitochondrial gene therapy would be expected to be useful and productive for the treatment of various diseases. To achieve such an innovative therapy, it will be necessary to deliver
Conclusions
In summary, we propose a novel strategy for the targeted delivery of macromolecules to a specific organelle (i.e., nucleus and mitochondria) based on the concept of stepwise membrane fusion, which is achieved using multicoated nanoparticles with endosome- and organelle-fusogenic lipid envelopes. At this time, a double-layered coating is added in a stepwise manner, based on the fusion of SUVs. Thus, in principle, only a particle with even numbers of lipid envelopes can be prepared. In the
Acknowledgments
This work was supported, in part by, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, Japan (NIBIO), Funding Program for Next Generation World-Leading Researchers (NEXT Program), a Grant-in-Aid for Young Scientists (A) and a Grant-in-Aid for Scientific Research (S) from the Ministry of Education, Culture, Sports, Science and Technology of Japanese Government (MEXT). H.A. is also supported by the Asahi Glass Foundation. We
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These authors contributed equally.