Gene Therapy Delivery Breakthrough: DNA Barcoding Improves Targeting
Researchers have made significant strides in enhancing the effectiveness of gene therapies by addressing a key challenge: ensuring therapeutic genes reach their intended targets within cells. A new study, spearheaded by Oregon State University College of Pharmacy graduate student Antony Jozić and published in Nature Biotechnology, details a novel method for tracking gene-carrying nanoparticles and optimizing their delivery.
The Challenge of Gene Therapy Delivery
Gene therapies hold immense promise for treating a wide range of diseases by introducing or modifying genetic material within a patient’s cells. However, a major hurdle has been the tendency for these therapies to be routed to lysosomes – the cell’s “trash and recycling centers” – where the therapeutic genetic material is broken down before it can exert its effect. Successful gene therapy requires bypassing this disposal system and reaching the appropriate cellular compartment where the genes can function.
DNA Barcoding: A New Tracking Method
The research team, led by Gaurav Sahay, professor of pharmaceutical sciences at Oregon State University, developed a DNA-based barcoding test. This innovative technique allows for the rapid and precise measurement, for the first time in living organisms, of which gene-carrying nanoparticles avoid destruction and which are discarded. The collaborative effort included scientists from Oregon Health & Science University (OHSU), Tennessee Technological University, Yeungnam University in South Korea, and the University of Brest in France.
“Once you can measure something, you can design around it,” explained Sahay. “Designs based on our measurements allow for new lipid nanoparticles capable of much more efficient delivery.”
How the Technology Works
The DNA barcoding system quantifies how efficiently different nanoparticle designs release their cargo. Lipid nanoparticles (LNPs) – tiny pieces of material ranging from one to 100-billionths of a meter – are used to deliver genetic material. A key component of these LNPs is an ionizable lipid, which changes its charge state depending on the acidity of its surroundings, aiding in both packaging the genetic material and interacting with cell membranes.
Using the barcoding system, researchers identified and validated a new class of lipid nanoparticles built around improved ionizable lipid systems. These new particles demonstrated safe and powerful gene editing at lower doses than current methods.
Key Findings and Implications
The study revealed that a primary obstacle in gene therapy is ensuring the cargo reaches the correct cellular location once inside the cell. This insight provides a roadmap for improving RNA and gene-editing medicines and reducing off-target effects. Researchers utilized LysoTag mice, which allow for the isolation of liver lysosomes, and their Lysosomal Barcoding method, finding that approximately 8% of the new BiP-20 LNPs reach the cytosol within 30 minutes of administration.
Loss of Rab7, a mediator of late endosomal maturation, increased LNP escape, according to lysosomal proteomics revealed mechanistic regulators of escape and BiP-20–induced alterations in endosomal maturation and recycling pathways.
Future Directions
The findings strongly validate the drug delivery science being developed at Oregon State University and highlight its growing leadership in the field. This breakthrough paves the way for more effective and safer gene therapies, offering hope for the treatment of a wide range of genetic diseases. The research was supported by the National Institutes of Health, the Defense Advanced Research Projects Agency, and the M.J. Murdock Charitable Trust.
Journal Reference: Jozić, A., et al. (2026). In vivo endosomal escape assay identifies mechanisms for efficient hepatic LNP delivery. Nature Biotechnology. DOI: 10.1038/s41587-026-03022-6