Novel nanocages for delivery of small interfering RNAs


April 19, 2023

(Nanowerk News) Small interfering RNAs (siRNAs) are a new therapy that can be used to treat various diseases. This has led to an increasing demand for a selective, efficient and safe mode of delivery of siRNA in cells. Now, in a collaboration between the Universities of Amsterdam and Leiden, researchers have developed a special molecular nanocage for siRNA delivery. In a paper that just came out in the journal chemistry (“Application of M12L24 nanocages as cell-specific siRNA delivery agents in vitro”) they present nanocage that is easy to prepare and display tunable siRNA delivery characteristics.

The nano cage was developed within the research group for Homogeneous, Supramolecular and Bio-Inspired catalysis from Prof. Joost Reek and Bas de Bruin at the Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, and further studies in Prof.’s group. Alexander Kros at the Leiden Chemical Institute. Schematic representation of the use of nanocages for siRNA delivery Schematic representation of the use of nanocages for siRNA delivery. On binding to siRNA (arrow A), nanocages with a typical diameter of 5–6 nanometers cluster into cage-RNA nanoparticles with a diameter of about 150 nanometers. It is small enough to enter the cell (arrow B) and deliver siRNA. (© Chemistry)

The researchers are motivated by the potential of siRNA in gene therapy, which requires an effective delivery system. They set out to develop nanocages with functional groups on the outside, making the cages capable of binding to siRNA strands.

Since binding is based on reversible binding, siRNAs can in principle be released in the cellular environment. To explore the delivery characteristics of their nanocage, the researchers conducted laboratory studies using a variety of human cancer cells.

Various nanocage

Nano cages are constructions of small molecular building blocks, called ditopic ligands, which are linked using metal atoms. A typical cage consists of 12 metal atoms and 24 ligands, hence the abbreviation M12L24. The researchers designed and synthesized five different ligands to form molecular cages with different siRNA binding affinities. They then prepared a series of siRNA-binding nanocage using platinum or palladium as the bridge metal. Palladium nanocage is less stable in the cellular environment, and decomposition is one mechanism of siRNA release.

After screening nanocage characteristics such as stability and siRNA-binding ability, delivery characteristics were tested in an assay based on siRNA-mediated Green Fluorescent Protein (GFP) silencing. Cage is used to deliver siRNA to human GFP-expressing cells, so fluorescence measurement can ensure successful delivery of siRNA. Two types of human cell lines were used: HeLa and U2Os. Four Pt12L24 nanocage structures Four Pt12L24 nanocage structures were investigated in this study, using platinum and various ligands. The first nanocage was also synthesized in a variant using palladium instead of platinum. (© Chemistry)

Cage composition determines siRNA delivery

To their surprise, the researchers were not only able to demonstrate satisfactory siRNA delivery, but also found remarkable differentiation depending on the metal used in the nanocage. Where is Pt. platinum based12L24 nanocage showed very effective siRNA delivery to U2OS cells, it showed little efficiency for HeLa. On the other hand, Pd12L24 the nanocage, derived from the same ligand building block, delivered siRNA to HeLa but not to U2OS. Such differentiation could not be observed in experiments when a commercially applied delivery system (lipofectamine) was used. They12L24 nanocages thus introduce the possibility of tuning the delivery characteristics of siRNA by tuning the composition of the nanocage.

In them chemistry paper, the researchers consider the unique cell selectivity feature of these nanoparticles a promising addition to the field of targeted RNA gene material delivery, whose full potential has yet to be uncovered. Although the current results were obtained in a highly controlled laboratory study, they hope that the delivery of tunable RNA from their nanocage will spawn highly desirable selective RNA nanomedicine developments in the future.


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