• Cheng-Long Zhu, Yi Wang, Shi-Chun Ren, Chang-Meng Yu, Xiao-Yang Sun, Zhi-Li Liu, Qian-Qian Li, De-Zhi Guo, Yu Chen, Jia You, and Jia-Feng Wang.
• Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China.
• Shock. 2024 Aug 12.

BackgroundSepsis, a complex and life-threatening disease, poses a significant global burden affecting over 48 million individuals. Recently, it has been reported that programmed death-ligand 1 (PD-L1) expressed on neutrophils is involved in both inflammatory organ dysfunction and immunoparalysis in sepsis. However, there is a dearth of strategies to specifically target PD-L1 in neutrophils in vivo.MethodsWe successfully developed two lipid nanoparticles (LNPs) specifically targeting neutrophils by delivering PD-L1 siRNA via neutrophil-specific antibodies and polypeptides. In vivo and in vitro experiments were performed to detect lipid nanoparticles into neutrophils. A mouse cecal ligation and puncture (CLP) model was used to detect neutrophil migration, neutrophil extracellular traps (NETs) level, and organ damage.ResultThe PD-L1 siRNA-loaded LNPs that target neutrophils suppressed inflammation, reduced the release of NETs, and inhibited T-lymphocyte apoptosis. This approach could help maintain homeostasis of both the immune and inflammatory responses during sepsis. Furthermore, the PD-L1 siRNA-loaded LNPs targeting neutrophils have the potential to ameliorate the multi-organ damage and lethality resulting from CLP.ConclusionsTaken together, our data identify a previously unknown drug delivery strategy targeting neutrophils, which represents a novel, safe, and effective approach to sepsis therapy.Copyright © 2024 by the Shock Society.

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