When It Comes To Cell Entry, Being Average Has Its Advantages

The secret, it seems, is to be average. Mid-sized nanomaterials – about 27 to 30 nanometers in diameter, or about 1,000 times thinner than a human hair – are optimal for cellular entry. In a research article to be posted this week in the online edition of the Proceedings of the National Academy of Sciences, the researchers note that this information is significant for developing gene and drug delivery tools as well as assessing the safety of nanotubes – infinitesimal bits of carbon and other materials used in everything from cameras to clothing.

“If you know how viruses get into cells, you know how to better design drugs to keep them out,” said L.B. Freund, professor of engineering at Brown. “Or if you do want molecules to get in – those in medication, say – knowing an optimal particle size for entry is also helpful.

“With nanotubes, we may be able to manufacture ones of a certain size to minimize chances that they’ll enter and perhaps harm cells.”

The type of cell entry the team studied is called receptor-mediated endocytosis.

Here’s how it happens: A virus or other particle arrives at the cell membrane. Protein receptors on the membrane act like hooks, grabbing onto hooks, or ligands, on the particle, much like two pieces of Velcro. As more and more chemical hooks are recruited for the task, the membrane wraps around the particle until it is completely engulfed. This is how herpes and influenza viruses get inside cells.

The process is believed usually to involve clathrin, a protein that coats the invader to aid in the Velcro-like fastening. Yet scientists have shown that flu viruses can invade cells even without a clathrin coat. Along with Huajian Gao and Wendong Shi from Max Planck, Freund created a mathematical model that can account for this. Particle size plays a key role. According to the team’s new model, cells take in viruses and other particles with a diameter of 27 to 30 nanometers more readily than ones that are larger or smaller. The faster the viruses are absorbed, the more rapidly they reproduce.

“Cells are simply optimizing the system,” Freund explained. “If a particle is too big, there may not be enough receptors to bind to the virus. If it is too small, it takes too much energy to bend the cell membrane as it engulfs the invader.”

When the team compared the implications of their theory to actual experimental observations with cells, they found broad agreement. “The theory is fundamentally sound – a significant outcome,” Freund said.

The Brown University Materials Research Science and Engineering Center, supported by the National Science Foundation, funded the work.