Researchers at the University of Nottingham have developed a modular platform for delivering RNA therapeutics that could offer an alternative to lipid nanoparticle systems used in current RNA vaccines. The approach uses supramolecular chemistry to assemble nanoscale RNA carriers from small cationic building blocks that self-organize through reversible host–guest interactions.
RNA therapeutics – including mRNA, siRNA, and self-amplifying RNA – require delivery systems that protect nucleic acids and enable cellular uptake. To address limitations of lipid nanoparticle platforms, the Nottingham team developed a supramolecular system in which cationic monomers assemble into polymer-like RNA carriers through reversible host–guest interactions with cucurbit[8]uril (CB[8]).
“These findings demonstrate a powerful, highly tuneable system with the potential to improve the delivery of genetic medicines,” said study lead Cameron Alexander in a press release.
When combined with RNA, the supramolecular polycations assemble into “supra-polyplex” nanoparticles through electrostatic interactions with the negatively charged nucleic acid backbone, allowing researchers to tune particle properties by varying monomer structure, including charge density, hydrophobicity, and branching.
The team synthesized libraries of oligoamine-based monomers and confirmed supramolecular polymer formation using NMR spectroscopy, including diffusion-ordered spectroscopy (DOSY), which indicated larger assemblies through reduced diffusion coefficients. The resulting particles, characterized using dynamic light scattering and electrophoretic mobility measurements, were typically below 150 nm with low polydispersity.
In cell-based assays, the nanoparticles delivered mRNA across several cell lines, with transfection efficiencies comparable to commercial reagents while maintaining high cellular viability. The system also proved adaptable to multiple RNA classes: siRNA formulations reduced expression of cancer-associated genes, while self-amplifying RNA constructs encoding influenza haemagglutinin triggered protective immune responses in mice challenged with H1N1.
“By offering a flexible alternative to current delivery technologies and enabling automated, scalable manufacture, this platform could support faster development of RNA-based vaccines during future infection outbreaks, improve the effectiveness of RNA therapies in cancer, and expand treatment options for many diseases,” Alexander said.
The authors note that further mechanistic studies will be required to understand how supramolecular architecture influences intracellular trafficking and RNA release.
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