Minimal “Self” Peptides That Inhibit Phagocytic Clearance and Enhance Delivery of Nanoparticles

Foreign particles and cells are rapidly cleared from the body by professional phagocytes that more often encounter and recognize "self" cells.  From studies of mice, CD47 appears to be a factor in multiple glycoprotein complexes that impede phagocytosis of self cells, with signaling of ‘self’ occurring through a highly polymorphic, species-specific receptor, SIRPα.  Here, short peptides were computationally designed from human-CD47, synthesized with anchoring groups, and attached to virus-size nanoparticles for injection into NOD.SCID (NSG) mice that are known to exhibit uniquely high compatibility with human cells.  The hCD47-peptides delay splenic clearance of particles by macrophages with an exponential advantage in persistent circulation, which we exploit in enhancing by >10-fold the near-infrared imaging of human tumor xenografts.  The affinity of hCD47 for NSG-SIRPα proves weak but within the broad range (0.1~5 mM) measured for ten constructed variants of human-SIRPα; several versions of hCD47-peptide are likewise shown to bind and potently inhibit nanoparticle uptake by a surprising cytoskeletal mechanism.  The reductionist approach reveals the importance and utility as well as some limits of a human ‘Marker of Self’.