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Extracellular vesicles incorporating retrovirus-like capsids for the enhanced packaging and systemic delivery of mRNA

Wenchao Gu1, Sijin Luozhong1, Simian Cai2

  • 1Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.

Nature Biomedical Engineering
|February 19, 2024
PubMed

Insights

Researchers engineered leukocytes to produce extracellular vesicles (EVs) that efficiently package and deliver messenger RNAs (mRNAs) across the blood-brain barrier (BBB) into neurons. This novel method enhances mRNA delivery for treating neuro-inflammatory diseases.

Area of Science:

  • Neuroscience
  • Biotechnology
  • Molecular Biology

Background:

  • The blood-brain barrier (BBB) poses a significant challenge for delivering therapeutics, including messenger RNAs (mRNAs), to diseased neurons.
  • Leukocyte-derived extracellular vesicles (EVs) show potential for crossing the BBB, but efficient mRNA loading and neuronal uptake remain difficult.

Purpose of the Study:

  • To develop a method for enhancing mRNA packaging into leukocyte-derived EVs.
  • To improve the ability of these engineered EVs to cross the BBB and be taken up by neurons.

Main Methods:

  • Engineering leukocytes to produce EVs incorporating retrovirus-like mRNA-packaging capsids using the activity-regulated cytoskeleton-associated (Arc) protein.
  • Transfecting leukocytes with DNA or RNA encoding Arc protein and Arc 5'-untranslated-region RNA elements.
  • Evaluating EV characteristics, BBB crossing, neuronal uptake, and therapeutic effects in a mouse model of neuro-inflammation.

Main Results:

  • Engineered EVs efficiently packaged and delivered long mRNAs into neurons.
  • These EVs incorporated endothelial adhesion molecules, crossed the BBB at inflammatory sites, and were endocytosed by neurons.
  • EVs derived from self-leukocytes were immunologically inert, enhancing mRNA delivery in a mouse model.

Conclusions:

  • Engineering leukocytes with mRNA-packaging capsids is a viable strategy to enhance EV-mediated mRNA delivery across the BBB.
  • This approach offers a promising, immune-tolerant method for delivering mRNA therapeutics to neurons in neuro-inflammatory conditions.

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