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Histone-inspired polymer assemblies (polyplexes) can regulate gene expression and subcellular transport in plasmids by harnessing the cellular machinery normally used for histone proteins. When grafted to polyplexes, histone tails promote nuclear accumulation, trigger plasmid DNA (pDNA) release, and enhance transcription. Herein, we developed multifunctional gold nanoparticles (AuNPs) decorated by histone motifs as histone-inspired scaffolds with improved pDNA binding, easy bioimaging, and increased potential for gene delivery and chromatin analysis applications. We hypothesized that polycationic AuNPs coupled to histone motifs would mimic the native presentation of these sequences on the histone octamer and thereby create structures with the capacity to both engage native histone effectors and condense pDNA into nucleosome-inspired nanostructures. AuNPs bearing ∼2 nm cores were prepared based on the well-established Brust-Schiffrin two-phase method involving tetrachloroaurate reduction in the presence of 1-pentanethiol. Solid phase peptide synthesis was employed to generate thiolated polycationic ligands and histone tail motifs, and the AuNPs and peptide ligands were combined in a two-step Murray place exchange reaction at various ratios to produce a collection of polycationic AuNPs modified with varying amounts of histone tails. Electron microscopy and thermal analyses demonstrated that these modified AuNPs exhibited tunable biochemical and biophysical properties that closely mimicked the properties of native histones. The histone-mimetic nanoscaffolds efficiently and sequence-specifically engaged histone effectors responsible for activating transcription. In addition, the nanoscaffolds condensed pDNA into complexes with high stability in the presence of physiological concentrations of heparin, a common extracellular polyanion. These combined properties of histone engagement and high stability led to a ∼6-fold enhancement in transfection efficiency as compared with typical polymeric transfection reagents, with the increased transfection efficiency correlated to the presence and amount of histone tails displayed on the surface of the nanoscaffolds. These findings demonstrate the utility of employing a biomimetic materials design approach to develop more effective and stable delivery vehicles for gene transfer and chromatin analysis applications.

Histone-Mimetic Gold Nanoparticles as Versatile Scaffolds for Gene Transfer and Chromatin Analysis