Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen 52074, Germany.
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena 07747, Germany.
ACS Nano. 2024 Oct 22;18(42):28866-28880. doi: 10.1021/acsnano.4c09054. Epub 2024 Oct 11.
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.
脓毒症的特征是免疫反应失调，且很难治疗。在盲肠结扎和穿刺（CLP）小鼠模型中，我们表明纳米药物可以通过靶向中性粒细胞来有效缓解全身和局部脓毒症事件。具体来说，通过用环状精氨酸-甘氨酸-天冬氨酸（cRGD）肽修饰临床阶段地塞米松脂质体的表面，我们促进它们与循环系统中的中性粒细胞结合，导致它们在原发性和继发性脓毒症部位的明显聚集。靶向 cRGD 的地塞米松脂质体可有效减少肠内脓毒症诱导部位和肝脏中不成熟的循环中性粒细胞和中性粒细胞细胞外陷阱。此外，它们在全身和局部减轻炎症细胞因子，同时保持全身 IL-10 水平，与对照脂质体和游离地塞米松相比，导致 IFN-γ/IL-10 比值降低。我们的策略从细胞水平解决了脓毒症问题，说明了将中性粒细胞既用作治疗靶点，又用作药物递送载体的应用。
