A signficant barrier to the applying of nanoparticles for precision drugs is the mononuclear phagocyte system (MPS), a various inhabitants of phagocytic cells primarily situated inside the liver, spleen and lymph nodes. Nearly all of nanoparticles are indiscriminantly cleared by the MPS by way of macropinocytosis earlier than reaching their supposed targets, leading to unwanted effects and decreased efficacy. Right here, we exhibit that the biodistribution and desired tissue accumulation of focused nanoparticles may be considerably enhanced by co-injection with polymeric micelles containing the actin depolymerizing agent latrunculin A. These macropinocytosis-inhibiting nanoparticles (MiNP) have been discovered to selectively inhibit non-specific uptake of a second “effector” nanoparticle in vitro with out impeding receptor-mediated endocytosis. In tumor bearing mice, co-injection with MiNP in a single multi-nanoparticle formulation considerably elevated the buildup of folate-receptor focused nanoparticles inside tumors. Moreover, subcutaneous co-administration with MiNP allowed effector nanoparticles to attain serum ranges that rivaled a typical intravenous injection. This impact was solely noticed if the effector nanoparticles have been injected inside 24 h following MiNP administration, indicating a brief avoidance of MPS cells. Co-injection with MiNP subsequently permits reversible evasion of the MPS for focused nanoparticles and presents a beforehand unexplored technique of modulating and enhancing nanoparticle biodstribution following subcutaneous administration.