Bio-Inspired Supramolecular Hybrid Dendrimers Self-Assembled from Low-Generation Peptide Dendrons for Highly Efficient Gene Delivery and Biological Tracking

Abstract

Currently, supramolecular self-assembly of dendrons and dendrimers emerges as a powerful and challenging strategy for developing sophisticated nanostructures with excellent performances. Here we report a supramolecular hybrid strategy to fabricate a bio-inspired dendritic system as a versatile delivery nanoplatform. With a rational design, dual-functionalized low-generation peptide dendrons (PDs) self-assemble onto inorganic nanoparticles via coordination interactions to generate multifunctional supramolecular hybrid dendrimers (SHDs). These SHDs exhibit well-defined nanostructure, arginine-rich peptide corona, and fluorescent signaling properties. As expected, our bio-inspired supramolecular hybrid strategy largely enhances the gene transfection efficiency of SHDs approximately 50 000-fold as compared to single PDs at the same R/P ratio. Meanwhile the bio-inspired SHDs also (i) provide low cytotoxicity and serum resistance in gene delivery; (ii) provide inherent fluorescence for tracking intracellular pathways including cellular uptake, endosomal escape, and gene release; and (iii) work as an alternative reference for monitoring desired protein expression. More importantly, in vivo animal experiments demonstrate that SHDs offer considerable gene transfection efficiency (in muscular tissue and in HepG2 tumor xenografts) and real-time bioimaging capabilities. These SHDs will likely stimulate studies on bio-inspired supramolecular hybrid dendritic systems for biomedical applications both in vitro and in vivo.

Self-assembly of pH-sensitive fluorinated peptide dendron functionalized dextran nanoparticles for on-demand intracellular drug delivery

“…1. Briefly, Generation 2 peptide dendron was synthesized using a divergent approach from H-Lys-OMe core and purified by column chromatography as reported before [26]. The fluorinated peptide dendron with four hydrophobic perfluoroalkyl chains was used as the hydrophobic segment.…”

Clustering Small Dendrimers into Nanoaggregates for Efficient DNA and siRNA Delivery with Minimal Toxicity

“…Second, low molecular weight dendrimers were grafted on biocompatible polymers or nanoparticles via stimuli-responsive linkages to "temporarily" generate materials with high charge density for effi cient and safe gene delivery. [17][18][19] Third, low molecular weight dendrimers were conjugated with lipids or fl uorous chains to generate amphiphilic materials, and these materials can self-assemble into cationic micelles via hydrophobic interactions or fl uorinefl uorine interactions. [20][21][22][23][24] After gene delivery, the micelles may disassemble into amphiphilic monomers with reduced cytotoxicity.…”

Charged group surface accessibility determines micelleplexes formation and cellular interaction

“…With the similar charge and size, the oligoarginine available on the micelle surface was expected to influence the ability of micelles to associate with or enter cells, but the total arginine and surface charge was not directly related to cellular interaction. 24, 40, 41 Only the available arginine content on the micelle surface correlated with the ability of the micelles to interact with cells. This further supports the idea that the oligoarginine on the mPEG-PLA-R 15 micelles was more available for interactions.…”