The Innate Immune System comprises the cells, soluble factors, and related mechanisms that defend the host from ‘Foreign', in a non-specific manner. Foreign includes invading microbes, as has been typical for eons, and also implanted or injected material systems. We have been exploring means to evade or delay clearance by the innate immune system, particularly shape, flexibility, and also ligand-specific mechanisms. Shape effects of drug delivery vehicles are largely unexplored, especially in vivo, but we have recently shown that flexible cylinders persist in vivo longer than spheres of identical composition (1). Flexible filomicelles increase both dosage and tumor-selective effects in vivo relative to spheres and thus appear promising as anticancer drug delivery systems. However, Macrophages – as the main cells of the Innate Immune System – still clear the injected carriers and limit dose; while at the same time, Macrophages somehow choose to leave our own ‘Self' cells alone. The Foreign vs Self decision certainly does NOT reside in steric repulsion by the glycocalyx or synthetic polymer ‘mimics' of it such as PEG. We have sought to address how Macrophages specifically recognize Self and to define its physicochemical limits, and we have focused on the cell-surface protein CD47 found on all of our own cells. We demonstrate a two-step procedure for recognizing intruders that helps avoid misdirected attacks. In the first step, which is well known, Macrophages adhere and begin engulfing objects studded with antibodies or plasma complement proteins that bind interlopers and will also bind to the body's own cells. But before a macrophage engulfs its target, it also checks for the second form of identification on all self cells, CD47. The ~100 aa extracellular domain of CD47 proves sufficient to induce a macrophage to disengage a cell from the same species or even a synthetic particle decorated with this domain (2). We detail the divergence in Foreign vs Self adhesive signaling mechanisms, the dependence on protein densities, and the particle size dependence for this fundamental facet of immunocompatability. REFERENCES: (1) Y. Geng, P. Dalhaimer, S. Cai, R. Tsai, M. Tewari, T. Minko, and D.E. Discher. 2007. Shape effects of filaments versus spherical particles in flow and drug delivery. Nature Nanotechnology 2: 249-255. (2) R. Tsai and D.E. Discher. 2008. Inhibition of ‘Self' Engulfment through deactivation of Myosin-II at the Phagocytic Synapse between Human Cells Journal of Cell Biology 180: 989-1003.