"I'm really excited about the translational potential of this work," said Dr. Anna Orr, the Nan and Stephen Swid Associate Professor of Frontotemporal Dementia Research in the Feil Family Brain and Mind Research Institute and member of the Appel Alzheimer's Disease Research Institute at Weill Cornell, who co-led the study. "We can now target specific mechanisms and go after the exact sites that are relevant for disease."

How Mitochondria and Free Radicals Affect the Brain

The research focused on mitochondria, the cell's energy-producing structures that convert food into usable energy. In the process, mitochondria release reactive oxygen species (ROS) -- molecules commonly known as free radicals. At normal levels, ROS help regulate essential cell functions, but excessive or poorly timed production can damage cells.

"Decades of research implicate mitochondrial ROS in neurodegenerative diseases," said Dr. Adam Orr, an assistant professor of research in neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell, who co-led the work.

Because of this connection, scientists have long tested antioxidants as a potential way to neutralize ROS and slow neurodegeneration. However, these clinical trials have largely failed. "That lack of success might be related to the inability of antioxidants to block ROS at their source and do so selectively without altering cell metabolism," Dr. Adam Orr explained.

A New Way to Stop Harmful Free Radicals

As a postdoctoral researcher, Dr. Orr developed a drug discovery platform designed to find molecules that specifically suppress ROS at individual mitochondrial sites while leaving normal functions intact. Through this approach, the team identified a group of compounds called S3QELs ("sequels"), which showed potential to block harmful ROS activity.

The researchers focused on Complex III, a mitochondrial site known for producing ROS that can leak into the rest of the cell, potentially causing damage. To their surprise, the excess ROS did not originate from neurons, but from astrocytes -- non-neuronal cells that provide structural and metabolic support to neurons.

"When we added S3QELs, we found significant neuronal protection but only in the presence of astrocytes," said Daniel Barnett, a graduate student in the Orr lab and the study's lead author. "This suggested that ROS coming from Complex III caused at least some of the neuronal pathology."

Further experiments showed that when astrocytes were exposed to disease-related factors such as inflammatory molecules or proteins linked to dementia (including amyloid-beta), their mitochondrial ROS production increased dramatically. Treatment with S3QELs suppressed much of this rise, while blocking other ROS sources did not have the same effect.

Barnett discovered that ROS oxidized certain immune and metabolic proteins involved in neurological disease, altering the activity of thousands of genes tied to inflammation and dementia.

"The precision of these mechanisms had not been previously appreciated, especially not in brain cells," said Dr. Anna Orr. "This suggests a very nuanced process in which specific triggers induce ROS from specific mitochondrial sites to affect specific targets."

Promising Results in Animal Models

When the team administered the S3QEL compound to mice engineered to model frontotemporal dementia, they observed reduced astrocyte activation, lower levels of inflammatory gene expression, and a decrease in a tau modification linked to dementia. Remarkably, these effects appeared even when treatment began after symptoms had already started.

Extended treatment improved lifespan, was well tolerated, and produced no significant side effects. Dr. Anna Orr attributes this to the compound's highly targeted action.

The team plans to continue developing the S3QEL compounds in collaboration with medicinal chemist Dr. Subhash Sinha, professor of research in neuroscience in the Brain and Mind Research Institute and member of the Appel Alzheimer's Disease Research Institute at Weill Cornell.

They also intend to investigate how disease-associated genes influence ROS production and whether certain genetic variants that raise or lower dementia risk might do so by altering mitochondrial ROS activity.

Changing How Scientists Think About Free Radicals

"The study has really changed our thinking about free radicals and opened up many new avenues of investigation," said Dr. Adam Orr. The potential of these findings to open new research approaches to inflammation and neurodegeneration is highlighted in the journal.

The scientists built a new form of the drug using spherical nucleic acids (SNAs), a type of nanostructure that embeds the drug directly into DNA strands coating tiny spheres. This re-engineering turned a weak, poorly dissolving chemotherapy drug into a highly targeted cancer-fighting agent that spares healthy tissue.

A Dramatic Boost Against Leukemia

The new therapy was tested in animals with acute myeloid leukemia (AML), a fast-growing and hard-to-treat blood cancer. Compared with the standard chemotherapy version, the SNA-based drug entered leukemia cells 12.5 times more efficiently, destroyed them up to 20,000 times more effectively, and slowed cancer progression 59-fold -- all without detectable side effects.

This success highlights the growing promise of structural nanomedicine, a field that precisely controls the composition and architecture of nanomedicines to improve how they interact with the human body. With seven SNA-based treatments already in clinical testing, researchers believe this approach could pave the way for new vaccines and therapies for cancers, infections, neurodegenerative disorders, and autoimmune diseases.

The findings were published on Oct. 29 in ACS Nano.

"Stopping Tumors in Their Tracks"

"In animal models, we demonstrated that we can stop tumors in their tracks," said Northwestern's Chad A. Mirkin, who led the research. "If this translates to human patients, it's a really exciting advance. It would mean more effective chemotherapy, better response rates, and fewer side effects. That's always the goal with any sort of cancer treatment."

Mirkin is a leading figure in chemistry and nanomedicine, serving as the George B. Rathmann Professor of Chemistry, Chemical and Biological Engineering, Biomedical Engineering, Materials Science and Engineering, and Medicine at Northwestern. He also directs the International Institute for Nanotechnology and is a member of the Robert H. Lurie Comprehensive Cancer Center.

Rethinking a Classic Chemotherapy Drug

For this study, Mirkin's team revisited 5-fluorouracil (5-Fu), a long-standing chemotherapy drug known for its limited efficiency and harsh side effects. Because it affects healthy cells as well as cancerous ones, 5-Fu can cause nausea, fatigue, and in rare cases, heart complications.

Mirkin explained that the issue lies not in the drug itself but in its poor solubility. Less than 1% dissolves in many biological fluids, meaning most of it never reaches its intended targets. When a drug cannot dissolve well, it clumps together or remains solid, preventing the body from absorbing it effectively.

"We all know that chemotherapy is often horribly toxic," Mirkin said. "But a lot of people don't realize it's also often poorly soluble, so we have to find ways to transform it into water soluble forms and deliver it effectively."

How Spherical Nucleic Acids Transform Drug Delivery

To overcome this limitation, the researchers turned to SNAs -- globular nanoparticles surrounded by dense shells of DNA or RNA. Cells readily recognize these structures and pull them inside. In this case, Mirkin's team chemically incorporated the chemotherapy molecules into the DNA strands themselves, creating a drug that cancer cells naturally absorb.

"Most cells have scavenger receptors on their surfaces," Mirkin explained. "But myeloid cells overexpress these receptors, so there are even more of them. If they recognize a molecule, then they will pull it into the cell. Instead of having to force their way into cells, SNAs are naturally taken up by these receptors."

Once inside, enzymes break down the DNA shell, releasing the chemotherapy payload directly into the cancer cell. This structural redesign completely changed how 5-Fu interacted with leukemia cells, dramatically increasing its effectiveness.

Precision Targeting With Minimal Harm

In mouse models, the new therapy nearly eliminated leukemia cells in the blood and spleen while significantly extending survival time. Because the SNAs selectively targeted AML cells, healthy tissues remained unharmed.

"Today's chemotherapeutics kill everything they encounter," Mirkin said. "So, they kill the cancer cells but also a lot of healthy cells. Our structural nanomedicine preferentially seeks out the myeloid cells. Instead of overwhelming the whole body with chemotherapy, it delivers a higher, more focused dose exactly where it's needed."

Next Steps Toward Clinical Trials

The research team now plans to test the approach in a larger group of small animal models before advancing to larger animals and, ultimately, human clinical trials, once additional funding becomes available.

The study, titled "Chemotherapeutic spherical nucleic acids," was supported by the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, with further support from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In two complementary studies, Timothy Jarome, an associate professor in the College of Agriculture and Life Sciences' School of Animal Sciences, and his graduate students used advanced gene-editing tools to target these molecular changes and improve memory performance in older rats. Rats are commonly used as models for understanding how memory declines with age.

"Memory loss affects more than a third of people over 70, and it's a major risk factor for Alzheimer's disease," said Jarome, who also serves in the School of Neuroscience. "This work shows that memory decline is linked to specific molecular changes that can be targeted and studied. If we can understand what's driving it at the molecular level, we can start to understand what goes wrong in dementia and eventually use that knowledge to guide new approaches to treatment."

Adjusting Memory Pathways in the Hippocampus and Amygdala

In the first study, published in Neuroscience and led by Jarome and doctoral student Yeeun Bae, the researchers investigated a molecular process called K63 polyubiquitination. This process acts like a tagging system that directs proteins inside brain cells on how to behave. When it functions properly, it helps neurons communicate effectively and form memories.

The researchers discovered that aging alters this process in two important brain regions. In the hippocampus, which is responsible for forming and retrieving memories, K63 polyubiquitination levels rise with age. Using a gene-editing system called CRISPR-dCas13, the team lowered those levels and observed improved memory in older rats.

In contrast, in the amygdala -- a region crucial for emotional memory -- K63 polyubiquitination decreases with age. When the researchers further reduced this activity, memory performance also improved.

"Together, these findings reveal the important functions of K63 polyubiquitination in the brain's aging process," Jarome explained. "In both regions, adjusting this one molecular process helped improve memory."

Reactivating a Dormant Gene to Improve Memory

The second study, published in the Brain Research Bulletin and led by Jarome and doctoral student Shannon Kincaid, focused on IGF2, a growth-factor gene known to support memory formation. As the brain gets older, IGF2 activity declines as the gene becomes chemically silenced within the hippocampus.

"IGF2 is one of a small number of genes in our DNA that's imprinted, which means it's expressed from only one parental copy," Jarome said. "When that single copy starts to shut down with age, you lose its benefit."

The team found that this silencing occurs through DNA methylation, a natural process that adds chemical tags to DNA, turning the gene off. Using the CRISPR-dCas9 gene-editing system, they removed these tags and successfully reactivated IGF2. Older rats showed significant memory improvement once the gene was turned back on.

"We essentially turned the gene back on," Jarome said. "When we did that, the older animals performed much better. Middle-aged animals that didn't yet have memory problems weren't affected, which tells us timing matters. You have to intervene when things start to go wrong."

Multiple Molecular Systems Influence Brain Aging

Together, these studies reveal that memory loss during aging doesn't result from a single cause. Instead, it involves several molecular systems that change over time.

"We tend to look at one molecule at a time, but the reality is that many things are happening at once," Jarome said. "If we want to understand why memory declines with age or why we develop Alzheimer's disease, we have to look at the broader picture."

Collaborative Research Led by Graduate Scientists

Both projects were driven by graduate researchers in Jarome's lab and carried out with collaborators at Rosalind Franklin University, Indiana University, and Penn State. Yeeun Bae led the K63 polyubiquitination study, while Shannon Kincaid led the IGF2 project.

"These projects represent the kind of graduate-led, collaborative research that defines our work," Jarome said. "Our students are deeply involved in designing experiments, analyzing data, and helping shape the scientific questions we pursue."

The research was funded by the National Institutes of Health and the American Federation for Aging Research.

"Everyone has some memory decline as they get older," Jarome added. "But when it becomes abnormal, the risk for Alzheimer's disease rises. What we're learning is that some of those changes happening at a molecular level can be corrected -- and that gives us a path forward to potential treatments."