Peptide nanofibers (PNFs) are one-dimensional assemblies of amphiphilic peptides in a cylindrical geometry. We postulated that peptide nanofibers (PNFs) can provide the tools for genetic intervention and be used for delivery of siRNA, as they can be engineered with positively charged amino acids that can electrostatically bind siRNA. The aim of this work was to investigate the use of PNFs as vectors for siRNA delivery and evaluate their potential in the therapy of neurodegenerative disorders. We designed a surfactant-like peptide (palmitoyl-GGGAAAKRK) able to self-assemble into PNFs, and demonstrated that complexes of PNF:siRNA are uptaken intracellularly and increase the residence time of siRNA in the brain. The biological activity of the complexes was investigated in vitro by analysing the down-regulation of the expression of a targeted protein (BCL2) and induction of apoptosis, and in vivo by analysing the relative gene expression upon stereotactic administration into a deep rat brain structure (the subthalamic nucleus). Gene expression levels of BCL2 mRNA showed that PNF:siBCL2 constructs were able to silence the target BCL2 in specific loci of the brain. Silencing of the BCL2 gene resulted in ablation of neuronal cell populations. Therefore, genetic interventions by PNF:siRNA complexes may lead to enhanced treatments of CNS pathologies.
- gene therapy