Abstract
The higher-order architecture observed in biological systems, like viruses, is very effective in nucleic acid transport. The replications of this system has been attempted with both synthetic and naturally occurring polymers with mixed results. Here we describe a peptide/siRNA quaternary complex that functions as an siRNA delivery system. The rational design of a peptide assembly is inspired by the viral capsids, but not derived from them. We selected the collagen peptide (COL) to provide the structural stability and the folding framework, and hybridize it with the cell penetrating peptide (CPP) that allows for effective penetration of biological barriers. The peptide/siRNA quaternary complex forms stoichiometric, 10 nm nanoparticles, that show fast cellular uptake (<30 min), effective siRNA release, and gene silencing. The complex provides capsid-like protection for siRNA against nucleases without being immunostimulatory, or cytotoxic. Our data suggests that delivery vehicles based on synthetic quaternary structures that exhibit higher-order architecture may be effective in improving delivery and release of nucleic acid cargo.
Highlights
The ability of siRNA to silence genes might lead to potentially transformative therapeutic strategies, but effective delivery continues to pose a significant challenge[1,2]
We have recently demonstrated that many of these challenges can be resolved by introducing architectural motifs via synthetic linking of Cell penetrating peptides (CPP) with a collagen peptide[15,16]
The combination of CPP and collagen peptide as independent domains of a hybrid peptide resulted in the formation of a new class of hybrids that exhibit a series of unusual properties
Summary
The ability of siRNA to silence genes might lead to potentially transformative therapeutic strategies, but effective delivery continues to pose a significant challenge[1,2]. We have recently demonstrated that many of these challenges can be resolved by introducing architectural motifs via synthetic linking of CPP with a collagen peptide[15,16]. This resulted in the formation of a triple helical nanocarrier that effectively delivered Paclitaxel to malignant cells[17]. We have previously shown that the temperature induced peptide folding of hybrid peptides into higher order structure, triple helix, allows for control selection of cellular delivery[16]. We hypothesized that the assembled synthetic CPP/collagen hybrid peptide (subunits) could result in the formation of higher-order architecture, a capsid-like vehicle for RNA delivery. This work presents the higher order assembly between multiple subunits and nucleic acid
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