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Introduction: Most nanomedicines are currently limited in their efficacy due to a sub-optimal biodistribution/accumulation in the target tissues. A large part of the administered dose remains useless due to the high rate of clearance by the mononuclear phagocytic system (mainly by Kupffer cells in liver). We designed a new approach based on the use of an engineered, biocompatible nanoparticle–the Nanoprimer–that is administered before the nanomedicine in order to transiently and specifically occupy the liver clearance pathways responsible for sub-optimal therapeutic bioavailability. The Nanoprimer's effect is only based on its specific physico-chemical properties, there is no active principal ingredient encapsulated in it. Here we demonstrate the ability of the Nanoprimer to redefine the bioavailability and efficacy of nanomedicines loaded with small molecules or nucleic acid. We evaluated the biodistribution and …