Aged-Signal-Eliciting Nanoparticles Stimulated Macrophage-Mediated Programmed Removal of Inflammatory Neutrophils

Excessive infiltration of activated neutrophils is regardedasa predominant cause of tissue injury in neutrophilic inflammation.Although programmed cell death like apoptosis maintains the homeostasisof activated neutrophils, this process is disrupted by an abnormalinflammatory response. Unlike endogenous calreticulin exposed duringapoptosis, exogenous calreticulin acts as an agedsignal and initiates premature macrophage-mediated programmed cellremoval (PrCR), which is independent of apoptosis. Here, we reporta nano-mediated strategy to stimulate the precise clearance of activatedneutrophils initiated with artificial aged signal and alleviated inflammation.Polymeric nanoparticles PC@PLGA were fabricated by cloaking poly(lactic-co-glycolic acid) (PLGA) with a hybrid membrane derivedfrom platelet-derived extracellular vesicles (PEVs, denoted by P)and the calreticulin-expressed membrane obtained from doxorubicin-treatedcells (denoted by C). P-selectin in PEVs favors PC@PLGA to anchoractivated neutrophils, while calreticulin mimics exogenous agedsignal secreted by macrophages to trigger PrCR. We showed that PC@PLGAspecifically targeted activated neutrophils and misled macrophagesto recognize them as aged neutrophils and then initiatedpremature PrCR and prevented proinflammatory response and tissue damagein a mouse model of acute lung injury and severe acute pancreatitis.The collective findings indicate the efficiency of specific eliminationof activated neutrophils with exogenous aged signal in improving inflammationtherapy.

Automated summary

This study reports a nano-mediated strategy to stimulate the precise clearance of activated neutrophils using an artificial aged signal, thus alleviating inflammation. The findings show that this strategy effectively targets and clears activated neutrophils, preventing inflammatory responses and tissue damage.