Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an alpha(1)-antitrypsin-derived peptide motif

While neutrophils are the first line of defence against infections and inflammation, their unrestricted recruitment and constant activation might result in prolonged inflammation and sharpening of specific pathological conditions. Here the authors develop a strategy to specifically target activated, pro-inflammatory neutrophils and neutrophil-platelet complexes to deliver therapeutics in the context of a murine model of venous thrombosis. Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We created a nanomedicine platform that uniquely utilizes an alpha(1)-antitrypsin-derived peptide to confer binding specificity to neutrophil elastase on activated neutrophils. Surface decoration with this peptide enabled specific anchorage of nanoparticles to activated neutrophils and platelet-neutrophil aggregates, in vitro and in vivo. Nanoparticle delivery of a model drug, hydroxychloroquine, demonstrated significant reduction of neutrophil activities in vitro and a therapeutic effect on murine venous thrombosis in vivo. This innovative approach of cell-specific and activation-state-specific targeting can be applied to several neutrophil-driven pathologies.