Engineered cargo-free nanoparticle decoys for phagocytic modulation of macrophages

Polymeric nanoparticles (NPs) are a versatile delivery platform for non-viral genetic therapies. However, a key shortcoming of polymeric NPs (and other non-viral delivery vehicles) is the often-high accumulation of NPs within the liver and the spleen after systemic intravenous (IV) administration in vivo. This phenomenon is largely the result of the mononuclear phagocytic system (MPS), a class of phagocytic cells responsible for native immune response and toxin clearance within the body. One strategy to overcome NP clearance by the MPS is the use of phagocytic modulating pre-treatments to intentionally and temporarily alter the phagocytic behavior of macrophages such that sequentially administered therapeutic NPs can be delivered to extrahepatic and extrasplenic tissues. Here, we explore the use cargo-free poly(lactic- co -glycolic acid) (PLGA) “decoy” NPs as pre-treatments for phagocytic evasion of sequentially administered therapeutic NPs. Analysis via flow cytometry and fluorescence microscopy reveal that cargo-free PLGA NPs significantly decrease uptake of subsequently administered therapeutic NPs by macrophages. Specifically, we conclude that variables such as size, surfactant composition, and timing of pre-treatment influence the behavior of cargo-free PLGA decoy NPs in modulating phagocytic activity of macrophages. In in vivo studies, we report decreased accumulation in the liver and increased deposition of therapeutic NPs in the lung with pre-administration of cargo-free decoy PLGA NPs. Together, these studies suggest pre-treatment with decoy NPs can reduce therapeutic NP clearance, with the potential to improve nanomedicine delivery capabilities for a wide range of therapeutics and disease targets. • Size, surfactant, dose, and timing of cargo-free PLGA NP decoy pre-treatments influence modulation of macrophage-mediated therapeutic NP phagocytosis. • Systemically administered cargo-free PLGA NP decoys increase subsequent therapeutic NP deposition in the lung in vivo. • Decoy pre-treatments could improve in vivo delivery for many non-viral genetic therapies.