Scientists are tackling major challenges in gene therapy and drug delivery

Imagine trying to poke a hole in the yolk of a raw egg without breaking the white. It sounds impossible, but researchers at the University of California, San Diego, have developed a technology that performs a similarly delicate task in living cells. They created a series of nanopillars that can break through the cell nucleus – the compartment where our DNA is located – without damaging the cell's outer membrane.

The study, published in Advanced functional materials, could open up new possibilities in gene therapy, which requires delivery of genetic material directly into the cell nucleus, as well as in drug delivery and other forms of precision medicine.

“We have developed a tool that can easily create a gateway to the core,” said Zeinab Jahed, a professor in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at UC San Diego and senior author of the study.

The core is inherently impenetrable. Its membrane is a heavily reinforced barrier that protects our genetic code and only allows certain molecules to pass through tightly controlled channels.

It's not easy to get to the core of something. Transporting drugs and genes across the nuclear membrane has long been an immense challenge.”

Zeinab Jahed, Professor, Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California – San Diego

Current methods for accessing the nucleus typically involve using a tiny needle to physically puncture both the nucleus and the cell. However, these methods are invasive and can only be used in small applications.

Jahed and her team, co-led by UC San Diego Nanoengineering Ph.D. Student Ali Sarikhani developed a non-disruptive solution. They constructed a series of nanopillars consisting of nanoscale cylindrical structures. When a cell is placed on these nanopillars, the cell nucleus wraps around the nanopillars, causing their membrane to curve. This induced curvature in turn causes tiny, self-sealing openings to temporarily form in the nuclear membrane. The outer membrane of the cell remains undamaged.

“This is exciting because we can selectively create these tiny breakthroughs in the nuclear membrane to go directly to the nucleus while the rest of the cell remains intact,” Jahed said.

In experiments, cells containing a fluorescent dye in their cell nuclei were placed on the nanopillars. The researchers observed that the dye passed from the cell nucleus into the cytoplasm but remained trapped in the cell. This suggested that only the nuclear membrane and not the cell membrane had been punctured. The researchers observed this effect in various cell types, including epithelial cells, cardiac muscle cells and fibroblasts.

The team is currently investigating the mechanisms behind this effect. “Understanding these details will be critical to optimizing the platform for clinical use and ensuring that it is both safe and effective for delivering genetic material into the nucleus,” Jahed said.