Lookup NU author(s): Dr Andrea Beyerle,
Professor Olaf Heidenreich
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Cell-penetrating peptides (CPP) are a promising strategy for inducing the cellular uptake of biomolecular cargos that otherwise only poorly enter cells, including siRNA. Recently, amphipathic CPP containing acyl and/or quinoline moieties were introduced that showed greatly enhanced delivery efficiency. However, the molecular basis of this increased activity is only poorly understood. Here, we performed a detailed analysis of the molecular and functional characteristics of siRNA-CPP nanoparticles for these derivatized amphipathic CPP and other cationic CPP, including the prototypic arginine-rich CPP nona-arginine and Tat. Dynamic light scattering demonstrated effective complexation of siRNA for all tested CPP. Optimal encapsulation of the siRNA was achieved at very similar molar ratios independent of peptide charge, except for CPP with an extreme high or low overall charge. Furthermore, in the presence of serum CPP-siRNA complexes acquired a negative zeta potential. Cell association was a necessary but not a sufficient criterion for activity. The most active CPP had the most negative zeta potential, and displayed the highest resistance towards decomplexation by serum, but were rather sensitive to decomplexation by polyanionic macromolecules. Our results provide a comprehensive molecular basis for the further development of peptide-based oligonucleotide transfection agents.
Author(s): van Asbeck AH, Beyerle A, McNeill H, Bovee-Geurts PHM, Lindberg S, Verdurmen WPR, Hällbrink M, Langel U, Heidenreich O, Brock R
Publication type: Article
Publication status: Published
Journal: ACS Nano
Print publication date: 21/04/2013
ISSN (print): 1936-0851
ISSN (electronic): 1936-086X
Publisher: American Chemical Society
Notes: Joint senior authorship OH and RB
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