siRNA Delivery Of Bolaamphiphiles: The Path To A Cure For Diabetes And Obesity

Researchers at the University of California, Irvine recently reported a new material to deliver RNA therapeutics to fat cells for gene therapy. Gene therapy has transformed biomedical research and paved the way for the treatment of hereditary diseases.  Gene therapy involves the delivery of foreign nucleic acids, such as DNA or RNA, into cells to control genes and ultimately alter protein expression. However, the application of this technology has been greatly hampered by a lack of safe and effective delivery methods, especially to adipocytes or fat cells.

Obesity presents a major public health crisis, contributing to increased risk of diabetes and heart disease. Gene therapy is a promising treatment for obesity, however, nucleic acid delivery to metabolic organs, such as adipose tissue, is challenging because of low delivery efficiency and high toxicity. Researchers in the Guan Lab, in collaboration with Prof. Qin Yang’s lab at the UC Irvine medical school, used the bolaamphiphile system they developed to deliver siRNA primary adipocyte (fat) and hepatocyte (liver) cells without disrupting the underlying function of the cells. Their findings were recently published in Biomaterials thematic issue “Chemistry of Biomaterials.”

Bolaamphiphiles are dumbbell-shaped structures that consist of hydrophilic head groups on either end connected to a hydrophobic core. In nature, bolaamphiphiles are within the cell membrane of archaebacteria. The unique structure of the bolaamphiphile enables it to form robust cellular membranes, allowing the archaebacteria to withstand harsh living conditions. Because of these unique properties, the bolaamphiphile is an attractive structure to use to create RNA delivery vehicles.

The specific bolaamphiphile system developed by the Guan Lab consists of natural amino acids on polar head groups connected to a fluorocarbon core. The natural amino acids give the vector functionality to bind RNA and enter the cell, while the fluorocarbon core promotes the assembly into nanoparticles.

To test the delivery efficiency of the system to metabolic cells, fluorescently labeled siRNA was delivered to adipocytes.  Adipocytes play a major role in lipid metabolism and part of the cause of obesity. However, it is difficult to study the cellular function of adipocytes because of the inefficient delivery of siRNA, a commonly used tool to study cells.

Using the labeled siRNA, the researchers studied the cellular uptake of bolaamphiphile/siRNA complexes along with the release of the siRNA cargo within the cells. The bolaamphiphile displayed high transfection efficiency, resulting in over a 70% reduction in gene expression.

In contrast to commonly-used commercially available products, the bolaamphiphile does not disrupt the underlying metabolic function of the cells. Additionally, in vivo tests in mice show that the bolaamphiphile system also is nontoxic and does not affect the hepatic or renal function of the animal.

Because the bolaamphiphile system has high delivery efficiency without negatively affecting lipid metabolism, it is a useful tool for studying different genes’ effect on lipid metabolism and diabetes through loss-of-function assays with siRNA. At the molecular level, many genes are involved in the metabolism of sugar and lipids. Any disruption of the sugar or lipid metabolism can lead to diabetes and other metabolic diseases. By using the bolaamphiphile system as a tool to further explore the role of these genes in adipocytes, a potential cure for diabetes and obesity can be discovered.

These findings are described in the article entitled Dendritic peptide bolaamphiphiles for siRNA delivery to primary adipocytes, recently published in the journal Biomaterials. This work was conducted by Alexander C. Eldredge, Mark E. Johnson, Yang Cao, Lin Zhang, Can Zhao, Zhengxia Liu, Qin Yang, and Zhibin Guan from the University of California, Irvine.