gene-rev-Saltzman - 2000 Nature America Inc...

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NATURE BIOTECHNOLOGY VOL 18 JANUARY 2000 33 REVIEW Synthetic DNA delivery systems Dan Luo and W. Mark Saltzman* School of Chemical Engineering, Cornell University, Ithaca, NY 14850. *Corresponding author ([email protected]). Received 18 September 1999; accepted 23 November 1999 The ability to safely and efficiently transfer foreign DNA into cells is a fundamental goal in biotechnol- ogy. Toward this end, rapid advances have recently been made in our understanding of mechanisms for DNA stability and transport within cells. Current synthetic DNA delivery systems are versatile and safe, but substantially less efficient than viruses. Indeed, most current systems address only one of the obsta- cles to DNA delivery by enhancing DNA uptake. In fact, the effectiveness of gene expression is also dependent on several additional factors, including the release of intracellular DNA, stability of DNA in the cytoplasm, unpackaging of the DNA–vector complex, and the targeting of DNA to the nucleus. Delivery systems of the future must fully accommodate all these processes to effectively shepherd DNA across the plasma membrane, through the hostile intracellular environment, and into the nucleus. Keywords; nonviral gene delivery, transfection, gene therapy, DNA, intracellular transport Over the past 30 years, DNA delivery, especially via the nonviral route (i.e., transfection), has become a powerful and popular research tool for elucidating gene structure, regulation, and function. Indeed, a recent search of the keyword “transfection” using the National Center for Biotechnology Information’s (NCBI; Rockville, MD) MEDLINE database ( yielded more than 50,000 papers. DNA delivery has also been pivotal in developing new approaches (e.g., gene therapy and DNA vaccination) for treating and controlling diseases that are likely to impact clinical medicine and biotechnology over the next few years. Before such applications can be realized, however, the relative inefficiency and cytotoxicity of modern synthetic DNA delivery systems must be addressed. Crucial to the success of DNA as a pharmaceutical or a basic research tool is transfection efficiency: in general practice, too few cells receive and express the exogenous DNA. Efficiency of transfec- tion is dependent on both the efficiency of DNA delivery (i.e., frac- tion of DNA molecules getting into the nucleus) and the efficiency of DNA expression (i.e., fraction of nuclear DNA molecules that undergo transcription). Although a greater efficiency of expression can usually be achieved with strong promoters and enhancers 1 , improvements in the efficiency of DNA delivery per se have been dif- ficult to achieve; thus, the number of cells receiving DNA in their nucleus is usually small. In addition, transfection efficiency in vitro and in vivo do not always correlate 2,3 , making translation of positive results in cell culture into animals even more difficult. Therefore, the challenge of DNA delivery is to develop a system that
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gene-rev-Saltzman - 2000 Nature America Inc...

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