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March 11, 2021

Van Lehn receives NSF CAREER Award to study nanoparticle properties for efficient cell entry

Written By: Jason Daley

Many of the most promising new treatments in medicine involve nanoparticles, or microscopic shells that can deliver finely targeted doses of drugs or other therapeutic molecules to various parts of the body. For example, nanoparticles are potentially valuable for the targeted delivery of nucleic acids directly into cells to repair faulty genes or compensate for them by producing missing proteins.

One of the big hurdles with these applications, however, is getting therapeutic molecules into the interior of a cell. Doing so requires nanomaterials to cross the cell membrane, which is a thin barrier separating the cell interior from the external environment. Most nanomaterials that attempt the crossing get trapped in compartments called “endosomes,” where they are digested or damage the cell. A few sub-10-nanometer particles made of certain materials are able to successfully cross the barrier and deliver the nucleic acids. However, it’s not clear why these nanoparticles are able to cross the cell membrane while others cannot.

That’s why Reid Van Lehn, Conway Assistant Professor in the Department of Chemical and Biological Engineering at the University of Wisconsin-Madison, plans to use funding from his National Science Foundation CAREER Award to investigate the characteristics of the nanoparticles that can successfully make the crossing.

“In this project, we want to use computational modeling and machine learning techniques to identify what the mechanisms are that permit nanoparticles to enter the cell interior without being trapped in endosomes,” says Van Lehn. “The other part of the project is taking that understanding and using it to guide the development of machine learning workflows that can then discover chemically accessible, available nanoparticles that can enter cells by crossing the cell membrane.”

Currently, the hunt for usable nanoparticles is relatively slow. Typically, researchers must synthesize a new nanoparticle, test to see if it enters cells, and eventually test it on mouse models. “Not only is the synthesis of the nanoparticles time-consuming, but you have to do these experiments with mice. This is a very laborious task,” says Van Lehn.

Instead, Van Lehn and his group plan to model parts of biological systems to understand how nanomaterials interact with them. “For example, we can model interactions with lipid bilayers that are just one component of a cell membrane. This computational approach will permit the creation of new types of nanoparticles much more quickly than would be possible through experiments alone, enabling the rational design of next-generation nanomaterials for diverse biomedical applications,” he says.

Besides crossing the cell membrane, Van Lehn says understanding of how nanomaterials interact with biological systems could enable other important advances. For instance, learning how these materials interact with proteins in the bloodstream could lead to a better understanding of immune response or could lead to the development of nanosensors of biomarkers to monitor or study certain diseases.

Van Lehn is also excited by the outreach component of his CAREER Award project. He plans to participate in the National Science Foundation’s Research Experience for Teachers in Engineering and Computer Science. The goal is to bring a high school teacher into his lab; that person can then share their experience in their own classroom—ideally inspiring college-bound students to consider computational modeling as a field of study.

Van Lehn’s group is also developing a slate of simple simulations aimed at students in grades six through 12 that show everyday interactions at the molecular scale, like how soap works. “This is a much more vibrant way of showing these processes than drawing them on a blackboard,” says Van Lehn, who hopes to make the visualizations available to all educators via UW-Madison’s NSF-funded Materials Research Science and Engineering Center.

Van Lehn hopes that the research on cell membranes will apply to other materials as well. “By the end of this five-year project, we want to have expanded the materials design toolkit through both fundamental understanding of cell membrane penetration and then design rules for enabling that behavior in additional classes of materials beyond just nanoparticles,” he says. “We can potentially take what we learn and apply it to polymers or other soft materials, engineered viruses and other materials with biomedical potential.”