Interactions of viruses and nano-carrier systems have been study extensively both in vitro and in vivo, but a major hurdle has been the inability of these foreign nanoparticles to evade recognition and rapid clearance by macrophages of the innate immune system. The longest circulating cells in the human body are red blood cells which are able to circulate without triggering such rapid clearance. Macrophages differentiate foreign vs. self through a ‘marker of self' found on the surface of red cells and other cells. We show that re-engineering of CD47 to be coupled either to a synthetic surface or expressed on viral particles can inhibit recognition by macrophages. Our results indicate that CD47 significantly reduces phagocyotsis by pathways that also apply with microparticles. Viral particles expressing the ‘self' protein have a lower level of transduction to macrophages leading to more specific targeting for gene delivery. Exploiting the body's own system of distinguishing foreign from ‘self' paves the way for avoiding toxic limits set by clearance and delivering more drug and genetic material to intended targets.