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Biological Chemistry

Peptide Fools Immune System Into Allowing Nanoparticles To Stick Around

Drug Delivery: ‘Don’t eat me’ signal allows nanoparticles to evade detection

by Elizabeth K. Wilson
February 21, 2013 | A version of this story appeared in Volume 91, Issue 8

Credit: Diego Pantano
Solving the structure of CD47 (blue and yellow) bound to SIRPα allowed researchers to design a smaller CD47 mimic.
A ribbon model of CD47 binding to SIRPalpha.
Credit: Diego Pantano
Solving the structure of CD47 (blue and yellow) bound to SIRPα allowed researchers to design a smaller CD47 mimic.

The immune system sometimes works too well, identifying useful things such as drugs, sutures, or pacemakers as unwanted invaders. Now, researchers have developed an artificial peptide modeled on a human protein that forestalls immune attack. Foreign particles and materials tagged with the peptide stay in the body without causing inflammatory responses, the team reports (Science, DOI: 10.1126/science.1229568).

University of Pennsylvania biophysical engineering professor Dennis E. Discher, graduate student Pia L. Rodriguez, and their colleagues modeled their peptide on the human protein CD47. This protein binds to a receptor known as SIRPα on the surface of macrophages, the immune cells responsible for engulfing invaders. CD47’s interaction with this receptor sends a signal to the macrophage to leave it alone.

The authors used computational techniques to design a 21-amino-acid peptide, which they call Self, that has the same SIRPα-binding characteristics as the larger CD47.

To test their peptide’s efficacy, the group attached the peptide to virus-sized polystyrene beads. They then injected them into mice genetically engineered to have humanlike SIRPα receptors. Mice injected with beads boasting the Self peptide had up to four times as many beads left in their systems after 20–30 minutes than did mice injected with unlabeled beads.

Discher’s group first discovered the “don’t eat me” signal triggered by CD47-SIRPα binding in 2008. When other researchers reported the structure of human CD47 bound to SIRPα, Discher’s group was then able to move forward with a designed mimic of the shielding protein.

Human CD47 can vary from person to person by a few amino acids, but the Self peptide is universal among humans. Anyone’s macrophages will accept it, Discher tells C&EN. It is also quickly synthesized. This work sets the stage for numerous experiments involving nanoparticles that deliver drugs and image tumors.

Discher “is looking ahead to potentially using this as a component of a therapeutic strategy where a drug is linked to a nanoparticle,” says Jayne Danska, professor in the immunology and medical biophysics departments at the University of Toronto. “It’s really high-quality work.”

Dennis E. Discher explains the role of macrophages in the immune system and explains how their approach allows nanoparticles to evade them.
Credit: Science/UPenn


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