Macrophages are immune cells that are capable of physically engulfing and clearing whole cells and particles. This process of phagocytosis is modulated by an important interaction between membrane protein CD47, present on all ‘self’ cells, and the macrophage immune-receptor SIRPα. Upon binding to CD47, SIRPα delivers “do not eat me” signals to the macrophage allowing the contact cell or particle to evade engulfment. Cancer cells, which are abnormal human cells, express, and sometimes over-express CD47, which is one mechanism used to escape immune clearance. While there has been success in targeting CD47 on cancer cells in the clinic, indiscriminate binding of anti-CD47 antibodies to CD47 on healthy blood cells is unavoidable, leading to toxic side effects such as anemia. Here, we describe the design and synthesis of short, multivalent, soluble peptide (nano-Self) antagonists engineered to block SIRPα on macrophages. We report potent activity of bivalent and tetravalent nano-Self peptides relative to the monovalent variants in enhancing macrophage engulfment of IgG-opsonized target cells. These multivalent nano-Self peptides associate with macrophages and also suppress tyrosine phosphorylation in macrophages, all consistent with inhibiting the macrophage ‘self’ signaling axis. These peptides potentially serve as novel biomolecular tools for macrophage immunotherapy, replacing anti-CD47 therapies currently being investigated in the clinic.