Novel Lipid Nanoparticle Design Boosts Gene Delivery Efficiency

Oregon State University College of Pharmacy scientists have achieved a major step forward in gene therapy by improving how genetic material and gene‑editing tools reach their intended destinations inside cells. The work, led by Gaurav Sahay, addresses a persistent challenge in drug delivery—ensuring that therapeutic genes avoid cellular disposal mechanisms. The study appeared in Nature Biotechnology.

When gene therapies enter cells, they frequently end up in lysosomes, the compartments that break down and recycle unwanted materials. Once trapped there, genetic cargo is destroyed before it can act. The key to successful therapy is preventing this fate and ensuring that the material travels to the correct cellular compartment. First author Antony Jozić and colleagues developed a way to measure, for the first time in living systems, which lipid nanoparticles deliver genes effectively and which are routed for degradation.

“Once you can measure something, you can design around it,” Sahay explained. “Designs based on our measurements allow for new lipid nanoparticles capable of much more efficient delivery.”

The researchers created a DNA‑based barcoding method that tracked lipid nanoparticle performance in mice. This system revealed how much of the genetic cargo reached its target versus how much was destroyed. “That allowed us to quantify how efficiently different nanoparticle designs release their cargo,” Jozić said. “It was a huge outcome for us and a particularly meaningful one for me after working on this for several years.”

Their measurements led to the identification of a new class of lipid nanoparticles that incorporate improved ionizable lipids—molecules that change charge depending on their environment. These lipids enhance both the packaging of genetic material and its ability to pass through cell membranes. The resulting nanoparticles enabled effective gene editing at significantly lower doses than existing methods. 

“The study also clearly demonstrated that the main problem with gene therapies is getting the cargo to the right part of the cell once it’s inside,” Sahay said. “This insight resolves a longstanding challenge in our field, to track genetic material inside the subcellular compartments within the cell in a living organism, and provides a road map for improving RNA and gene-editing medicines and reducing off-target effects.”