Peptide-Enhanced Nucleic Acid Delivery
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Peptide-Enhanced Nucleic Acid Delivery
Jamie M. Bergen and Suzie H. Pun Abstract Numerous barriers, both extracellular and intracellular, hinder successful and efficient nonviral nucleic acid delivery. Due to their small size and ability to specifically recognize and interact with molecular targets, peptides can be incorporated as modular elements into synthetic nucleic acid delivery systems to overcome many of these barriers. Three classes of peptides that have frequently been integrated as components in nucleic acid delivery systems include cell-penetrating peptides (CPPs), endosomal release peptides, and nuclear localization sequences (NLSs). Various additional classes of peptides show promise for enhancing nucleic acid delivery by targeting cell surface receptors, inhibiting nuclease activity, and directing nucleic acids toward intracellular targets. In addition to a review of the various existing approaches to peptide-enhanced nucleic acid delivery, this article will discuss strategies for the development of new peptides and approaches for the incorporation of these peptides into nucleic acid delivery systems. Keywords: biomedical materials, nucleic acid delivery, peptides.
Introduction Significant progress has been made toward the development of materials-based synthetic systems that deliver therapeutic nucleic acids to cells. For many applications, however, the maximum delivery efficiencies achieved by synthetic, nonviral systems are sub-therapeutic. One strategy for improving the efficacy of nonviral nucleic acid delivery involves incorporating short, bioactive peptides into synthetic delivery systems. Nonviral delivery vehicles that incorporate peptides to assist in overcoming or bypassing the major barriers to nucleic acid delivery may achieve higher efficiencies than unmodified vehicles. While the development of peptides that enhance nucleic acid delivery has focused primarily on cell targeting, plasma membrane translocation (using cellpenetrating peptides), endosomal release (using pH-sensitive peptides), and nuclear entry (using nuclear localization sequences) (see Figure 1), new peptides have recently been developed that are capable of preventing nucleic acid degradation and targeting nucleic acids to specific intracellular organelles. After a review of the various types of peptides that show promise for enhancing nucleic MRS BULLETIN • VOLUME 30 • SEPTEMBER 2005
acid delivery, this article will discuss strategies for the development of new peptides, as well as approaches for their incorporation into nonviral nucleic acid delivery systems.
Cell-Penetrating Peptides The plasma membrane is an effective barrier against the entry of large, anionic nucleic acid molecules into cells. To overcome this, nonviral delivery systems typically condense nucleic acids by electrostatic interactions within cationic carriers, and the resulting nanoparticles are internalized by the cell in vesicles. However, unless the nucleic acids escape these vesicles, they progress to the hostile environment of lysosomal compart
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