Gene Therapy Breakthrough: New Nanoparticle Designs Enhance Delivery and Efficacy

PORTLAND, Ore. – Researchers have made significant strides in improving the effectiveness of gene therapies by addressing a key challenge: consistently delivering therapeutic genes and gene-editing tools to the correct location within cells. The findings, published today in Nature Biotechnology, offer a promising path toward more efficient and safer genetic treatments.

The Challenge of Gene Delivery

Gene therapies introduce or modify genetic material within a patient’s cells to treat diseases. Although, a major hurdle has been the tendency of these therapies to be routed to lysosomes – the cell’s waste disposal and recycling centers – where the therapeutic genetic material is broken down before it can function. Successful gene therapy requires bypassing this disposal system and reaching the cellular compartments where the genetic material can exert its therapeutic effect.

A Novel Approach to Measuring Delivery Efficiency

The study, spearheaded by Antony Jozić, a graduate student at Oregon State University College of Pharmacy, developed a new method to measure, for the first time in living organisms, which gene-carrying nanoparticles avoid destruction and which are discarded. This breakthrough was achieved under the guidance of Gaurav Sahay, professor of pharmaceutical sciences.

“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.”

DNA-Based Barcoding Reveals Nanoparticle Fate

The research team, collaborating with scientists from Oregon Health & Science University (OHSU), Tennessee Technological University, Yeungnam University in South Korea and the University of Brest in France, created a DNA-based barcoding test. This test, used in mouse models, quantified how much genetic material carried by lipid nanoparticles (LNPs) was degraded versus how much successfully reached its target. LNPs are tiny particles, ranging from one to 100-billionths of a meter in size, composed of lipids (fatty acids and similar organic compounds).

“That allowed us to quantify how efficiently different nanoparticle designs release their cargo,” said Jozić. “It was a huge outcome for us and a particularly meaningful one for me after working on this for several years.”

Optimizing Lipid Nanoparticles for Enhanced Delivery

The researchers focused on ionizable lipids, which can change their charge depending on the acidity of their surroundings. These lipids play a crucial role in both packaging genetic material and interacting with cell membranes. By leveraging the measurements enabled by the barcoding system, they identified and validated a new class of lipid nanoparticles built around improved ionizable lipid systems.

The new particles demonstrated powerful gene editing at significantly lower doses compared to existing delivery methods. The study likewise highlighted that the primary challenge in gene therapy lies in directing the therapeutic cargo to the correct cellular location once inside the cell.

“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,” Sahay added.

Future Directions

This research, supported by the National Institutes of Health, the Defense Advanced Research Projects Agency, and the M.J. Murdock Charitable Trust, represents a significant step forward in gene therapy. The development of more efficient and targeted delivery systems promises to unlock the full potential of genetic medicine, offering new hope for treating a wide range of diseases.