Researchers have developed an effective gene therapy approach that has shown promise in treating potentially lethal bacterial infections.
A team led by scientists from the University of Minnesota has discovered that a silicon nantherapeutic can deliver short interfering RNA (siRNA) that targets immune system cells and ultimately protects the body’s system against drug-resistant bacterial infections. The porous silicon nanoparticles contain an outer sheath of homing peptides and fusogenic liposome.
The researchers used a siRNA gene therapeutic approach to enhance the ability of some of the innate immune cells to attack the bacteria, while simultaneously shutting down the immune system’s inflammatory response that interferes with the recovery process.
To achieve this, the team generated a porous nanoparticle host that protects the siRNA payload from premature degradation in the bloodstream. They also discovered a peptide that selectively targets macrophage cells—a type of white blood cell that attacks foreign microbes and signals an invader is present.
The researchers also engineered a fusogenic lipid—a chemical coating that enables the nanoparticle to penetrate into the macrophage and deliver its gene therapeutic to the proper compartments in the cell.
In the past, it has proved difficult to deliver siRNA in the body. However, the researchers found that siRNA therapy could produce a full recovery from an otherwise lethal bacterial infection when they infected mice with a lethal dose of Staph. Aureus pneumonia. The therapy rescued 100 percent of the mice tested.
“A short strand of peptide can recognize macrophages, an important immune cell type, selectively in the infection site,” University of Minnesota researcher Hongbo Pang said in a statement. “In combination with nanomaterial of unique advantages as drug carriers, we could deliver gene therapeutics efficiently to where they are needed, and achieve a full recovery from a lethal bacterial infection.”
According to the study, a major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. The nanosystem is able to bypass endocytosis and achieve potent gene knockdown efficacy.
An estimated 23,000 deaths in the U.S. and 700,000 worldwide result from antimicrobial resistance. A Wellcome Trust 2016 study predicted the present rate of emergence of new virulent strains would outstrip the U.S. Food and Drug Administration approval rate for new antimicrobial agents by 2050, where the deaths from antimicrobial resistant strains will exceed the deaths resulting from cancer.
The researchers believe that the new approach could be effective for a number of bacterial infections, including emerging strains.
“This study perfectly demonstrates the great potential of targeted nanotechnology in treating various human diseases,” Pang said.
Michael Sailor from the University of California, San Diego, led and is the corresponding author of the study. Other research team members consisted of Erkki Ruoslahti with the Sanford Burnham Medical Discovery Institute and Ji-Ho Park with the Korea Advanced Institute of Science and Technology.
The study was published in Nature Communications.