Challenging the Consensus Led Dalhaimer to New Treatment Path

Nanoparticle (NP) therapy, or the use of nanometer-scale technologies, holds great potential for the personalized treatment of diseases arising from genetic factors, like Alzheimer's Disease, and from environmental factors, like obesity. Recently, a great deal of research has focused on targeting NPs to specific tissues—for example, having a chemotherapy NP bind specifically to a protein that appears only on tumor cells so that healthy cells are not affected.

Treating those diseases largely relies on a researcher's ability to design an NP that reaches the target. Unfortunately, a meta-analysis in 2016 revealed that less than one percent of injected NPs reach most target tissues.

"Over the past 30 years, our approach to improving the localization of NPs in the body has been to improve the design of the NP using increasingly advanced chemistries," said Paul Dalhaimer, an associate professor in the Department of Chemical and Biomolecular Engineering (CBE) at the University of Tennessee, Knoxville. "But the more complex the NP becomes—the more its properties diverge from the chemistries our bodies evolved with—the more difficult it is to predict how our bodies will respond to it."

Last year, Dalhaimer and other researchers in his lab published surprising results about how the body reacts to a common NP, revealing unknown complexities about the human immune system and creating an intriguing new possibility for NP therapies.

Challenging Assumptions in Immunology

Most bioengineers designing NP therapies will add poly-ethylene-glycol (PEG) to the exteriors of their NPs. PEG is difficult for proteins to bind, so these "PEGylated" NPs are—theoretically—less likely to be caught by blood serum proteins like antibodies.

The leading theory for low NP delivery success was that after being injected, PEGylated NPs would attract antibodies, which would then transport the NP to macrophages (cells that engulf and destroy anything the immune system perceives as foreign).

However, NPs localize to macrophages too fast for the antibody binding theory to be true.

"There was a mismatch in the timing," Dalhaimer said. "In the data, NPs were localizing to the macrophages much faster than the mouse could make an antibody against the novel chemistries of the NP. Some other mechanism was missing from our understanding."

Dalhaimer and his team began investigating the binding kinetics of NPs to macrophages. To their surprise, they discovered that PEG itself has an affinity for macrophages.

"I was skeptical when I saw the result," Dalhaimer admitted. "I thought it might be an error."

After searching the literature, Dalhaimer found a supplemental figure in the back of an unrelated 2013 Nature article that showed PEG bound to a macrophage surface protein. Reassured that their findings were real, Dalhaimer and his team published their breakthrough in early 2024.

Rather than giving up on NP therapy or trying to find a way to route NPs around macrophages, Dalhaimer has taken an unexpected route—using the PEGylated NP itself as therapy.

The Delivery System Becomes the Drug

The 2024 study, headed by Dalhaimer's former student Monirah Asoudeh (CBE Ph.D. '22), had been part of Dalhaimer's efforts to improve the delivery of anti-inflammatory NPs in individuals with obesity, which causes constant inflammation throughout the body.

"Obesity is a big issue throughout rural Tennessee, where a lot of the food is coming from gas stations and fast food," Dalhaimer said. "Fighting obesity-related inflammation involves both improving nutrition and lowering inflammation in the currently obese population. That second half is where our lab's work comes in."

Since he joined the CBE faculty in 2009, Dalhaimer has been investigating how NPs can be used to alter the function of macrophages, which are deeply involved in the body's inflammation response. Macrophages are also very concentrated in the liver, one of the organs most responsible for pro-inflammatory signals.

When his group discovered that PEG binds directly to macrophages, Dalhaimer saw an important opportunity.

"Macrophages were once thought of as one-dimensional cells that only cleared foreign objects. We are learning that they are much more sophisticated and are responsible for much of our adult health, including inflammation response, tissue repair, and aging," he said. "For us, if the PEGylated NP goes to a macrophage, that's not a drawback; it's a head start on treating many diseases caused by macrophage malfunction."

Happily, the 2024 study also revealed that pure PEG binding to a macrophage had the exact effect Dalhaimer's team had been working toward.

"By luck, the PEG receptor on the surface of macrophages is anti-inflammatory," said Dalhaimer. "We see that PEGylated NPs cause an anti-inflammatory response when they bind it. Because the PEGylated NP causes a physiological response, the whole PEGylated NP becomes the drug."

Dalhaimer and his team are currently studying whether PEGylated NP injections are effective at reducing liver inflammation in obese and aged mice. Hopefully, as liver macrophages stop sending pro-inflammatory signals, inflammation will also be reduced throughout the body.

"We're investigating whether PEGylated NP treatment can reduce pro-inflammatory signals system-wide," Dalhaimer said. "Perhaps, eventually, we can even improve the health of the liver."

More information:
www.sciencedirect.com/science/ … ii/S0168365923008039

Provided by University of Tennessee at Knoxville