UCLA researchers in the Department of Chemistry & Biochemistry have recently developed a novel gene delivery system with both improved precision and long-term effectiveness over current tools used for gene therapy.
BACKGROUND: Gene therapies typically use delivery tools such as exosomal or liposomal nanoparticles due to their high bioavailability and low immunogenicity, meaning they are readily taken up by target cells and are nontoxic. Alternatively, virus-like particles (VLPs) offer a more stable and precise mode of gene delivery. VLPs are non-infectious vehicles comprising of a protective lipid bilayer and/or proteinaceous capsid enveloping single-stranded RNA cargo, such as mRNA. Transmembrane glycoproteins incorporated on the VLPs are recognized by the target cells which then take up the VLP and its cargo, but do not produce new VLPs and so are non-infectious. Limitations of utilizing VLPs for gene therapies include high potential immunogenicity due to their viral-like genomes, and difficulty in large-scale production. Novel strategies are needed to overcome these limitations so that VLPs can be used for their advantages as longer-lasting gene therapies.
INNOVATION: Researchers at UCLA led by Dr. William Gelbart have developed a novel gene delivery system that provides greater therapeutic potential over existing delivery systems by engineering enveloped virus-like particles with both optimized targeting and non-toxic properties. Furthermore, the produced particles are precisely controlled as consistent, uniform structures due to the component origins being derived from the most highly-ordered and thermodynamically stable enveloped virus. Lastly, the delivery system is scalable, or high-yielding, as the mode of production is in cellulo rather than in vitro. The therapeutic RNA cargo is self-replicating, while the VLPs themselves are not, thus providing a reliably high-yielding drug delivery system with a potentially low immune response.
POTENTIAL APPLICATIONS:
- Targeted gene therapy
- Gene therapy research
- Delivery tool for immunotherapies, such as T cell therapy
- Delivery tool for mRNA vaccines
ADVANTAGES:
- In cellulo synthesis provides greater scalability compared to in vitro synthesis
- Provides a precisely controlled and homogenous delivery system for therapeutic RNA
- Avoids immunotoxicity due to non-replication of the packaging particles
- Enhanced yield and specificity of genetic cargo within the producer cells
- Wide targetability of any conjugatable ligands, for example antibodies
- Potentially applicable to T cell therapies and mRNA vaccines
DEVELOPMENT-TO-DATE: This therapeutic delivery system has been demonstrated and is currently being validated in vitro.
Related Papers (from the inventors only):
Rees F. Garmann, William M. Gelbart. 2026. Packaging of Single-Stranded RNA in Viruses and Virus-Like Particles. Annual Review Biochemistry. 95:In press. https://doi.org/10.1146/annurev-biochem-080525-105928
Keywords: Gene delivery, alphavirus, virus-like particles, VLPs, mRNA therapy, gene therapy, cell-targeting ligands, Sindbis vector, in cellulo synthesis, mammalian virus, protein nucleocaspids, viral capsids, mRNA nanotechnology, enveloped viruses, non-infectious replicon