Innate immune cell modulation using cargo-less nanoparticles to ameliorate severe inflammation

Abstract

Abstract 1.6 million people are diagnosed with sepsis each year in the US with a mortality rate of 25-30%. Attempts to improve patient outcomes include strategies to abrogate the overexaggerated immune response seen in sepsis but have thus far failed. It has been hypothesized that these have collectively been unsuccessful as they target a single molecular pathway and do not address redundancies in immune activation pathways. We have shown that nanomaterials are inherently potent immunomodulators that can broadly reduce the release of inflammatory cytokines. As such, we aimed to understand the physical and biological mechanisms that underlie the macrophage response to nanomaterials in the setting of LPS stimulation. PLA-based particle formulations were prepared with similar sizes (~500 nm) and different charges depending on surfactant (−50 to −20 mV). Particles prepared with an anionic surfactant (PEMA) are more effective than those with a neutral surfactant (PVA) at inhibiting inflammatory cytokine secretion in a manner independent of NF-κB activation. Additional studies show that PLA-PVA particles colocalize with TLR agonist at the cell surface, while agonist localization was abolished in cells treated with PLA-PEMA particles. LPS-induced endotoxemia studies show that i.p. administration of PLA-PEMA particles prior to challenge with LPS significantly improved survival of mice compared to those challenged with LPS alone. This work contributes to the fundamental understanding of the physicochemical properties of biomaterials and their modulation of immune cell responsiveness towards activating stimuli and suggests that nanomaterials are novel immune modulators in cases of acute and potentially life-threatening inflammation.