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Dynamic carriers for therapeutic RNA delivery.

Simone Berger1,2, Ulrich Lächelt2,3, Ernst Wagner1,2

  • 1Department of Pharmacy, Pharmaceutical Biotechnology, Ludwig-Maximilians-Universität Munich, 81377 Munich, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|March 4, 2024
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Dynamic RNA delivery carriers protect cargo, then release it. Virus-inspired designs leverage nanoparticle-host interactions for effective RNA delivery by responding to biological cues.

Keywords:
LNPRNAlipoplexpolyplexsynthetic virus

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Area of Science:

  • Biomaterials Science
  • Nanotechnology
  • Molecular Biology

Background:

  • Effective RNA delivery requires carriers that stabilize and protect therapeutic RNA during transit and release it in a bioactive form.
  • Current RNA carriers include cationic lipids, xenopeptides, and polycations, each with limitations in dynamic response.
  • Understanding nanoparticle-host interactions is crucial for optimizing RNA delivery systems.

Purpose of the Study:

  • To highlight virus-inspired dynamic processes for potent RNA delivery.
  • To explore how nanocarriers can dynamically respond to the biological microenvironment.
  • To identify key host-derived cues that trigger nanocarrier responses.

Main Methods:

  • Review and perspective on existing and emerging RNA delivery carrier technologies.
  • Analysis of virus-inspired dynamic processes and their application to synthetic nanocarriers.
  • Investigation of host-derived cues (pH, ion concentration, redox potential, proteins, receptors, enzymes) and their recognition by nanocarriers.

Main Results:

  • Discovery of distinct virus-inspired dynamic processes that enhance RNA delivery.
  • Demonstration that nanocarriers can be designed to recognize and respond to specific biological microenvironmental cues.
  • Identification of dynamic chemical designs (cleavable bonds, alterable properties, assembly-disassembly) as key to responsive RNA delivery.

Conclusions:

  • Dynamic, responsive nanocarriers inspired by viruses offer a promising strategy for potent RNA delivery.
  • Tailoring nanocarrier design to specific biological cues is essential for efficient cargo release and therapeutic efficacy.
  • Future RNA delivery systems will likely incorporate sophisticated dynamic and responsive elements for improved performance.