Nature Medicine | Spoonful of Medicine

Bundled RNA balls silence brain cancer gene expression

Mirkin lab, Northwestern

Scientists have developed a nanotechnology-based way to silence a key genetic switch involved in the formation of glioblastoma brain cancer. The technique, which delayed tumor growth in mice, consists of an injection of synthetic balls of RNA with a gold nanoparticle core. Researchers think similarly engineered RNA blobs, called spherical nucleic acids (SNAs), could eventually be used to treat Alzheimer’s disease and other neurodegenerative ailments.

“We are really excited about this,” says Alexander Stegh, a cancer biologist at the Northwestern University Feinberg School of Medicine in Chicago who helped develop the new cancer-killing SNA platform. “It’s a really novel approach.”

One of the biggest challenges for researchers wishing to treat brain-related diseases is crossing the blood-brain barrier, a separation of circulating blood that blocks bacteria and large molecules from entering the brain. Recent attempts to address this issue in brain cancer have involved injecting gene-silencing RNA directly into brain tumors. This method, called RNA interference (RNAi), is designed to neutralize the expression of important oncogenes. But injecting RNA through the skull poses a number of safety and logistical issues, and is inefficient in cases involving more than one tumor site.

To address this problem, Stegh teamed up with Northwestern chemist Chad Mirkin to engineer SNAs that serve as RNAi delivery vehicles capable of crossing the blood-brain barrier. They packed the gold-cored spheres full of RNA molecules designed to silence the expression of Bcl2L12an oncogene that inhibits cancer-suppressing pathways and is over expressed in the brains of people with glioblastoma compared with healthy brains. The researchers injected the SNAs into the tails of glioma-bearing mice. The RNA balls then traveled through the bloodstream to various organs, including the brain. “The really interesting thing is that the SNAs have a GPS-like affinity for cancer cells that causes them to selectively accumulate in the tumor,” Stegh says. The tumor “acts like a sponge,” he explains, allowing the SNAs to enter through its “leaky blood vessels.”

Inside the tumor, the RNAs engaged scavenger receptors on the surface of cancer cells. There, the unique three-dimensional architecture of the SNAs—an orientation imparted by the gold core scaffolding—allowed the therapy to turn on the cells’ ability to internalize the RNA balls. Once inside the cells, the RNA molecules bound to the complementary strands of messenger RNA encoded by the Bcl2L12 oncogene. This induced specific degradation of the Bcl2L12-encoded messenger RNA, reducing protein level expression and increasing mouse survival time by several days, on average, compared with sham-treated controls. The study was published online today in Science Translational Medicine.

For Stegh, the most important aspect of his research team’s innovation is the fact that the SNAs were able to travel to the cancer cells despite being injected outside the brain. “Other studies have used nanomaterials to treat brain tumors, but this is the first study that shows this works in systemic applications as well,” he says. David Corey, a pharmacologist from the University of Texas Southwestern Medical Center in Dallas, agrees. “The interest is the delivery method,” says Corey, who was not involved in the study.

Since the mice did not appear to experience any adverse effects from the therapy, the next step in the team’s research will be to see if the SNAs can be combined with first-line chemotherapy treatment. “We know that our target gene plays an important role in regulating the cell death that is induced by these therapies,” Stegh says. So, a combined approach could eventually produce a much more powerful therapeutic effect.

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    KONG DERICK NJIKEH said:

    Great work. Nanomedicine is the furture hope for the curative treatment of cancers and other genetic disorders. This work shows a great progress in this field.