Engineered human cells improve gene editing delivery using virus-like particles

Genome-wide screening in human producer cells has identified genetic pathways that control virus-like particle assembly, offering a scalable route to improve gene editing delivery systems for therapeutic use

Researchers have reported a novel strategy to enhance the production and performance of virus-like particles used to deliver gene editing tools, by focusing on the human cells that manufacture these delivery systems rather than the particles themselves.

Gene editing has emerged as a powerful approach to target the genetic causes of disease. However, to deliver the editing machinery into the correct cells with sufficient efficiency, safety and scale remains a central challenge. Virus-like particles have attracted considerable interest as delivery vehicles because they mimic the structure and cell-entry capability of viruses while lacking viral genetic material. Scientists have adapted these particles to carry gene editing components and to enable precise modification within target cells.

A study led by Dr. Aditya Raguram and researcher Diana Ly at the Whitehead Institute, Cambridge, Massachusetts, USA, has shifted attention towards the cellular systems responsible for assembling these particles. The research has introduced a platform to identify genes within producer cells that influence particle assembly, with the aim to engineer cells that generate more effective delivery vehicles.

“We can engineer the particles as much as we want, but if we do not understand how the producer cells actually make them, we are limited in how much we can improve production,” said Raguram.

The research team conducted a genome-wide screen to identify genes that influence virus-like particle production. They generated a diverse population of human producer cells, each with a different gene switched off. Because the particles incorporate fragments of genetic material from their host cells during assembly, each particle effectively carried a molecular barcode that identified which gene had been disabled in its cell of origin. By sequencing these barcodes, the researchers could determine which gene disruptions enhanced or impaired particle production.

“One thing that surprised me was how clearly the search was able to highlight specific pathways that play a major role in the production of these particles,” said Ly.

The analysis revealed that disruption of a single gene produced the most pronounced increase in particle output. This gene typically acts to limit the production of guide RNA, the short RNA molecules that direct gene editing enzymes to specific genomic targets. When the gene was disabled, cells produced higher quantities of guide RNA, and each virus-like particle carried a greater functional payload.

The researchers demonstrated that this improvement was not restricted to a single system. Engineered producer cells showed enhanced performance across multiple gene editing platforms and particle designs, including delivery systems developed by other laboratories. This consistency suggested that optimisation of guide RNA loading may offer a broadly applicable route to improve delivery efficiency.

“Because guide RNA loading is essentially universal across different cargo types and particle systems, this improvement could prove broadly useful beyond the particles we have developed,” said Raguram.

The study also identified a subset of genes with more complex roles. Disabling these genes increased production of structural proteins required to assemble the particles but reduced their ability to deliver cargo effectively. In specialised manufacturing contexts where protein availability constrains production, however, these same genetic modifications increased overall delivery potency.

The team has continued to expand the screening platform to explore additional cellular mechanisms that influence particle assembly. Rather than restrict analysis to single-gene disruptions, the researchers have begun to investigate more complex cellular changes to refine production strategies further. They have also shared engineered cell lines with collaborators and have initiated partnerships to improve delivery into clinically relevant cell types, including immune cells and neurons.

“This delivery challenge is one of the last remaining bottlenecks that limits the widespread application of gene editing technologies,” said Raguram.

“To solve the production challenges could move virus-like particles closer to readiness for clinical use,” he added.

The longer-term objective is to translate these improvements into therapies for genetic disease. By increasing both the efficiency and reliability of delivery systems, the approach could help to unlock the therapeutic potential of gene editing across a wide range of conditions.

The Whitehead Institute – founded in 1982 – has established a reputation for fundamental research in genetics, genomics, cancer biology and developmental biology. The institute maintains an affiliation with Massachusetts Institute of Technology but operates independently in both its governance and research direction.