For this first systematic examination of the effect of shape on phagocytosis, Champion and Mitragotri synthesized their own IgG-coated polystyrene particles, using natural macrophage targets as inspirations (spherical and rod-shaped particles mimic bacteria, flat discs resemble red blood cells, etc). Macrophages ingested each and every shape, but only if the target was initially encountered from the correct side—the one that required the most gradual expansion of the membrane as it englufed the particle.
“There is a right and a wrong shape from the macrophage's perspective,” says Mitragotri. “If it attaches at the right angle, from the right side, it can take in something as large as itself.” From the wrong side, however, not even a particle 1/100th that size was taken in.
Mitragotri compares the phagocytosis of a rod to eating a sub sandwich. Starting off with the narrow end makes eating a snap, but if you tried eating it from the long, blunt side, you would have much more difficulty.
For us, that difficulty is opening our mouths wide enough. For the macrophage, the limitation seems to be actin-based membrane expansion. In successful phagocytosis, an actin cup formed underneath the object being engulfed and pushed the macrophage membrane forward uniformly. In unsuccessful attempts, actin cups did not form, and membrane movements were random and uneven, resembling cell spreading. The difference may reflect the inability of actin to expand uniformly to cover the steeply increasing circumference of the object.
The findings can be used to design drug carriers that offer some control over the degree of their phagocytosis. Vaccines, which should be taken in immediately, would do well in spherical vehicles. Drugs meant for sustained release, however, may be better offered in rods, which are only efficiently internalized when they meet macrophages head-on.
Natural macrophage targets have much more complex surface chemistry than polystyrene particles, so Mitragotri expects there will be differences between real and artificial systems. But, he says, “shape will certainly come into the picture.”