Mastering Dendrimer Self‐Assembly for Efficient siRNA Delivery: From Conceptual Design to In Vivo Efficient Gene Silencing

Abstract

Self-assembly is a fundamental concept and a powerful approach in molecular science. However, creating functional materials with the desired properties through self-assembly remains challenging. In this work, through a combination of experimental and computational approaches, we report on the self-assembly of small amphiphilic dendrons into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high-generation dendrimers. We demonstrate that, with the optimal balance of hydrophobicity and hydrophilicity, one of the self-assembled nanomicellar systems, totally devoid of toxic side effects, is able to deliver small interfering RNA (siRNA) and achieve effective gene silencing both in cells - including the highly refractory human hematopoietic CD34+ stem cells - and in vivo, thus paving the way for future biomedical implementation. This work presents a case study of the concept of generating functional supramolecular dendrimers via self-assembly. The ability of carefully designed and gauged building blocks to assemble into supramolecular structures opens new perspectives on the design of self-assembling nanosystems for complex and functional applications.

Cationic micelle: A promising nanocarrier for gene delivery with high transfection efficiency

“…For example, the self‐assembly of small amphiphilic dendrons (such as PAMAM) into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high‐generation dendrimers has been reported. With the optimal balance of hydrophobicity and hydrophilicity, the self‐assembled micellar systems, totally devoid of toxic side effects, are able to deliver the gene into the cell and achieve effective gene silencing both in vitro and in vivo . Also, recent advances in synthetic polymer chemistry and biotechnology have allowed the development of polymeric micelles with integrated smart functions, such as environmental sensitivity and specific target ability .…”

“…The molecular component, physical and chemical properties, charge density and particle size of the micelles also have significant effects on the stability of polyplexes and/or their performances in gene delivery. The optimal balance of the hydrophobic and hydrophilic components critically controlls their self‐organization, which in turn significantly affects their performance in small‐interfering RNA (siRNA) delivery (Figure ) . These amphiphilic dendrons self‐assemble and generate supramolecular nanostructures that resemble and mimicke the structurally well‐defined covalent high‐generation dendrimers.…”

“…Schematic presentation of self‐assembly of amphiphilic dendrons into supramolecular dendrimers to resemble covalent high‐generation dendrimers for functional siRNA delivery and gene silencing. Reproduced with permission…”

“…With the optimal balance of hydrophobicity and hydrophilicity, the self-assembled micellar systems, totally devoid of toxic side effects, are able to deliver the gene into the cell and achieve effective gene silencing both in vitro and in vivo. 35 Also, recent advances in synthetic polymer chemistry and biotechnology have allowed the development of polymeric micelles with integrated smart functions, such as environmental sensitivity and specific target ability. 1,2,6,7,11 Thus, there is a strong impetus for the development of polymeric cationic micelles that achieve successful gene delivery.…”

Mix and Match: Coassembly of Amphiphilic Dendrimers and Phospholipids Creates Robust, Modular, and Controllable Interfaces

“…10–12 They can assemble into supra-molecular nanostructures and can be loaded with therapeutic cargos, either through hydrophobic encapsulation within the interior of a dendrimer nanomicelle 11 or via electrostatic interaction with the charged amine functionalities on the dendrimer surface. 12–14 While these assemblies have proved highly effective compared to traditional lipid or dendrimer vectors, interest is growing around the coassembly of synthetic compounds with naturally occurring phospholipids for the assembled constructs’ potential to demonstrate both natural and tunable biophysical properties. 15–18 In this line, we investigated the coassembly processes of amphiphilic dendrimers 1 – 3 with palmitoyloleoylphosphocholine (POPC), a major component of the plasma membrane (Figure 1).…”