Atomically Precise Au14V1 Clusters Selectively Block the Neutrophil Elastase-NETosis Axis

Abstract Neutrophil elastase (NE) is a key driver of neutrophil-mediated inflammation and tissue injury across diverse diseases. However, current NE inhibitors often lack sufficient target selectivity, limiting their therapeutic efficacy in suppressing inflammation and promoting organ repair. Here, we report that single-atom V doping programs atomically precise Au15 clusters into a relatively selective and potent NE inhibitor. The ultrasmall size of Au14V1 enables selective accommodation within the NE binding pocket. Multiscale mechanistic analyses demonstrated that Au14V1 inhibits NE through a reversible mixed inhibition mechanism with an inhibition rate of 87.6%, while exhibiting minimal activity toward closely related proteases, highlighting its preferential inhibition toward NE. In LPS- and CLP-induced systemic inflammatory injury models, Au14V1 reduced NE activity and NET formation, alleviated oxidative stress and inflammatory responses, mitigated tissue injury, and improved survival. These findings establish a single-atom engineering strategy for developing selective enzyme modulators and precise therapy targeting the NE-NETosis axis.