Specific Molecular Nanocages for siRNA Delivery


Small interfering RNAs (siRNAs) are a new therapy that can be used to treat various diseases. This has increased the need for safe, effective and targeted siRNA delivery methods in cells. Researcher from University of Amsterdam and Leiden have now fabricated a molecular nanocage specifically for siRNA delivery.

Specific Molecular 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. Pictures are taken from paper. Image Credit: University of Amsterdam

They presented an easy-to-prepare nanocage with a customizable siRNA delivery feature in a study published in the journal chemistry.

The research team of homogeneous, supramolecular and bio-inspired catalysis led by Prof. Joost Reek and Prof. Bas de Bruin at the Van’t Hoff Institute for Molecular Sciences at the University of Amsterdam developed nanocages.

Prof Alexander Kros’ group at the Leiden Institute of Chemistry continues the study. The researchers are motivated by the potential of siRNA in gene therapy, which requires an effective delivery system.

In order to enable the cage to bind to the siRNA strands, they set out to create a nanocage containing the functional group on the outside. SiRNA can theoretically be released in the cellular environment because its binding is based on reversible binding.

The scientists conducted laboratory experiments using some human cancer cells to investigate the delivery properties of their nanocages.

Multiple Nano Cage

Nano cages are structures made of small molecular building blocks known as ditopic ligands held together by metal atoms. The acronym M12L24 refers to the conventional cage, which has 12 metal atoms and 24 ligands. To create molecular cages with varying siRNA binding affinities, the researchers developed and synthesized five different ligands.

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 evaluating the stability and siRNA-binding ability of the nanocage, the delivery properties were tested in experiments based on siRNA-mediated Green Fluorescent Protein (GFP) silencing.

Fluorescence measurements were performed after siRNA was successfully delivered to human GFP-expressing cells using cages. The HeLa and U2Os cell lines from the human species were both used.

Cage Composition Determines siRNA Delivery

To their surprise, the researchers were able to demonstrate effective siRNA delivery and also found that there were marked differences based on the metal used in the nanocage. The platinum-based Pt12L24 nanocage delivered siRNA to U2OS cells excellently but had minimal effect on HeLa cells.

The palladium-contained Pd12L24 nanocage, made from the same ligand building blocks, delivered siRNA to HeLa but not to U2OS. This difference could not be seen in trials using a commercially available delivery technology (lipofectamine).

The M12L24 nanocage thus introduces the possibility of tuning the delivery characteristics of siRNA by tuning the composition of the nanocage.

The researchers believe that the cell’s unique selectivity feature of the nanoparticles is a promising contribution to targeted delivery of RNA gene material, whose full potential has yet to be realized.

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.

Journal Reference:

Bobilev, EO, et al. (2023) Application of M12L24 nanocages as cell-specific siRNA delivery agents in vitro. chemistry. doi:10.1016/j.chempr.2023.03.018.



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