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RNA Structure01:23

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High-throughput Synthesis of Carbohydrates and Functionalization of Polyanhydride Nanoparticles
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Polyanion Chemistry Engineers Ternary RNA Nanoparticle Structure/Function from the Inside-Out.

Lijun Hu1,2, David J Peeler1,2,3, Tianyi Jin4

  • 1Kavli Institute for Nanoscience Discovery, Department of Physiology, Anatomy and Genetics, Department of Engineering Science, University of Oxford, Oxford OX1 3QU, United Kingdom.

ACS Nano
|January 27, 2026
PubMed
Summary

Researchers engineered novel ternary polyelectrolyte nanoparticles (TNPs) using specific polyanions for enhanced nucleic acid delivery. These TNPs demonstrate improved stability and targeted delivery, offering a promising alternative to lipid nanoparticles.

Keywords:
PET-RAFTSANShigh throughputmolecular dynamicsself-amplifying RNAstructure/function

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Area of Science:

  • Biomaterials Science
  • Nanotechnology
  • Drug Delivery Systems

Background:

  • Lipid nanoparticles (LNPs) are common for nucleic acid delivery, but polymeric alternatives like ternary polyelectrolyte nanoparticles (TNPs) offer potential for targeted delivery.
  • Understanding the role of polyanion chemistry in TNP stability, protein binding, and transfection efficiency is crucial for developing advanced delivery systems.

Purpose of the Study:

  • To engineer hydrophobic polyanions that provide TNPs with a negative surface charge and enhanced extracellular stability for targeted nucleic acid delivery.
  • To systematically investigate how PEG architecture and polyanion chemistry influence TNP structure and function.

Main Methods:

  • Synthesis of chemically diverse PEGylated polyanions to coat self-amplifying RNA (saRNA) polyplexes (PP).
  • High-throughput stability assays and Small Angle Neutron Scattering (SANS) for structural studies.
  • Molecular Dynamics (MD) simulations and in vitro cell studies for functional analysis.

Main Results:

  • PEG5k-bl-polyanion5k formulations resulted in small, pH-responsive core-shell TNPs.
  • A lead formulation (TNP5) with balanced hydrophobicity and charge density demonstrated effective extracellular stability and intracellular unpackaging.
  • MD simulations indicated polyanions control TNP function by managing water exclusion and protein binding.

Conclusions:

  • Polyanion engineering is key to controlling TNP structure and function for efficient RNA delivery.
  • The study establishes a framework for high-throughput engineering of pH-responsive nanoparticles to overcome biological barriers in RNA delivery.
  • Chemically diverse polyanions offer a tunable platform for developing targeted nucleic acid delivery systems.