Neutrophil Hitchhiking Enhances Liposomal Dexamethasone Therapy of Sepsis
Rashmi V. Mathur, Sara Elsafy, Adrian T. Press, J.C.P.Klaasse E. Brück, Mathias W. Hornef, Lukas Märtin, Tobias Schürholz, Gernot Marx, Matthias Bartneck, Fabian Kießling, Josbert M. Metselaar, Gert Storm, Twan Lammers, Alexandros Marios Sofias, Patrick Koczera
Abstract
Sepsis is characterized by a dysregulated immune response and is very difficult to treat. In the cecal ligation and puncture (CLP) mouse model, we show that nanomedicines can effectively alleviate systemic and local septic events by targeting neutrophils. Specifically, by decorating the surface of clinical-stage dexamethasone liposomes with cyclic arginine-glycine-aspartic acid (cRGD) peptides, we promote their engagement with neutrophils in the systemic circulation, leading to their prominent accumulation at primary and secondary sepsis sites. cRGD-targeted dexamethasone liposomes potently reduce immature circulating neutrophils and neutrophil extracellular traps in intestinal sepsis induction sites and the liver. Additionally, they mitigate inflammatory cytokines systemically and locally while preserving systemic IL-10 levels, contributing to lower IFN-γ/IL-10 ratios as compared to control liposomes and free dexamethasone. Our strategy addresses sepsis at the cellular level, illustrating the use of neutrophils both as a therapeutic target and as a chariot for drug delivery.