(443d) Leveraging Polymerized Salicylic Acid Microparticles in Acute Inflammatory Conditions: Shutting of Neutrophil Extracellular Traps (NETs) from the inside Out

Neutrophils can contribute to inflammatory disease propagation via innate mechanisms intended for inflammation resolution. For example, neutrophil extracellular traps (NETs) are necessary for trapping pathogens but can contribute to clot formation and blood flow restriction, ischemia and ultimately lead to organ damage. Currently, there are no therapeutics in the clinic that directly target NETs despite the known involvement of NETs contributing to mortality and increased disease severity. Vascular-deployed particle-based therapeutics are a novel and robust alternative to traditional small-molecule drugs by enhancing drug delivery to cells of interest, such as neutrophils. In this work, we designed a high-throughput assay to investigate the immunomodulatory behavior and functionality of salicylic acid‐based polymer-based particle therapeutics against NETosis in human neutrophils. We found that not only does polymeric composition play a role, but particle size can also influence rates of NETosis. Further, salicylate-based polymeric (Poly-SA) particles were found to functionally inhibit NETosis via interrupting intracellular pathways. Importantly, In vivo assays Poly-SA particles reduce multiple inflammatory cytokines in the airway and bacterial load in the bloodstream in a live bacteria lung infection model of ARDS, drastically improving survival. It is observed that phagocytosis of the Poly-SA microparticles, with salicylic acid in the polymer backbone, alters the neutrophil surface expression of adhesion molecules. Given the proven safety profile of the microparticle degradation products—salicylic acid and adipic acid—it is anticipated that the Poly-SA particles represent a therapeutic strategy with a rare opportunity for rapid clinical translation.