OSU researchers turn natural cellular process into drug delivery system

Production of Particles

Scientists at The Ohio State University have created a new gene-therapy technique that transforms human cells into mass producers of tiny nano-sized particles full of genetic material. The researchers believe that the gene therapy strategy could help to reverse disease processes, such as Alzheimer’s and Parkinson’s disease, according to an article published in Nature Biomedical Engineering.

While undertaken as proof of concept, the experimental therapy resulted in slower tumor growth and longer survival in mice with gliomas, which make up approximately 80 percent of malignant brain tumors in humans. The technique uses exosomes, fluid-filled sacs that cells release to communicate with other cells. Exosomes are being recognized as biologically friendly carriers of therapeutic materials, because they are plentiful and not involved in an immune response. Still, researchers need to find a way to fit big genetic instructions inside tiny bodies to have a therapeutic effect.

The patented technology in the new method gets donated human cells, such as adult stem cells, to excrete millions of exosomes. After they are collected and purified, they act as nanocarriers containing a drug. When injected into the bloodstream, these carriers know where in the body to find a specific target.

According to senior study author L. James Lee, professor emeritus of chemical and biomolecular engineering at The Ohio State University, “Think of them like Christmas gifts. The gift is inside a wrapped container that is postage paid and ready to go. They are gifts that keep on giving. This is a Mother Nature-induced therapeutic nanoparticle.”

In 2017, the researchers discovered a regenerative medicine process called tissue nanotransfection (TNT) that uses a nanotechnology-based chip to deliver biological cargo directly into skin. This action converts adult stem cells into any cell type needed for treatment in a patient’s body. Delving into the mechanism behind TNT’s success, the researchers found that exosomes were the secret to delivering regenerative cells to tissue under the skin. In this study the technology was adapted into a technique first author Zhaogang Yang, a former Ohio State postdoctoral researcher now at the University of Texas Southwestern Medical Center, called cellular nanoporation.

The researchers put 1 million donated cells, including mesenchymal cells from human fat, on a nano-engineered silicon wafer and used an electrical stimulus to inject synthetic DNA into the donor cells. The DNA force-feeding caused the cells to eject unwanted material as part of DNA transcribed messenger RNA and repair holes poked in their membranes.

As Lee explained, “They kill two birds with one stone. They fix the leakage to the cell membrane and dump the garbage out. The garbage bag they throw out is the exosome. What’s expelled from the cell is our drug.”

The electrical stimulation provided a thousand-fold increase of therapeutic genes in many exosomes released by the cells, showing that the technology is scalable to produce enough nanoparticles for use in humans. To accomplish gene therapy, researchers need to know which genes must be delivered to repair a medical problem. The researchers tested the results on glioma brain tumors by using a gene called PTEN, a cancer-suppressor gene. Mutations of PTEN that turn off that suppression role enable cancer cells to grow unchecked.

The synthetic DNA force-fed to donor cells is copied into a new molecule that includes messenger RNA, containing the instructions for producing a specific protein. Each exosome bubble containing messenger RNA is transformed into a nanoparticle ready for transport, with no worries about the blood-brain barrier.

Lee concluded, “The advantage of this is there is no toxicity, nothing to provoke an immune response. Exosomes go almost everywhere in the body, including passing the blood-brain barrier. Most drugs can’t go to the brain.”