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Directed evolution of engineered virus-like particles with improved production and transduction efficiencies
Aditya Raguram1,2,3,4, Meirui An5,6,7, Paul Z Chen5,6,7,8
1Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA. araguram@wi.mit.edu.
Nature Biotechnology
|November 13, 2024
Summary
Engineered virus-like particles (eVLPs) were evolved using a novel barcoded system to improve their delivery capabilities. The resulting fifth-generation eVLPs show enhanced potency for delivering genetic materials to human cells.
Area of Science:
- Biotechnology
- Molecular Biology
- Virology
Background:
- Engineered virus-like particles (eVLPs) are advanced platforms for transient delivery of therapeutic molecules like proteins and RNAs.
- Current eVLP technology requires optimization for enhanced production and cellular transduction efficiencies.
Purpose of the Study:
- To develop a laboratory evolution system for discovering eVLP variants with superior properties.
- To engineer eVLP capsids with improved production and gene delivery efficiencies in human cells.
Main Methods:
- A system utilizing barcoded guide RNAs within DNA-free eVLP cargos was employed for library labeling.
- Directed evolution strategies were applied to select for eVLP variants with enhanced production and transduction.
- Beneficial capsid mutations were combined to create advanced-generation eVLPs.
Main Results:
- A fifth-generation (v5) eVLP was developed, demonstrating a 2-4 fold increase in delivery potency to mammalian cells compared to v4 eVLPs.
- Mutations in v5 eVLPs optimize the packaging and delivery of ribonucleoprotein cargos.
- Significant alterations in eVLP capsid structure were observed in the evolved variants.
Conclusions:
- The barcoded eVLP evolution system effectively identifies variants with improved properties.
- The developed v5 eVLPs represent a significant advancement in transient gene delivery vehicles.
- This approach holds promise for the future development of enhanced eVLP-based therapeutics.
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