In Situ Assembly of Transformable Monopeptide on Activated Neutrophils Attenuates NETs‐Induced Hepatocellular Carcinoma Metastasis by Disrupting NE Nuclear Translocation

Abstract Neutrophil extracellular traps (NETs) released by activated neutrophils in the tumor microenvironment has emerged as a pivotal mediator in promoting tumor metastasis. The alteration of the subcellular localization of neutrophil elastase (NE) is crucial for NETs formation. The majority of NE (≈80%) translocate from azurophilic granules to the nucleus, facilitating histone degradation and chromatin decondensation. A few NE are transported to the cell membrane, a unique feature of activated neutrophils that distinguishes them from other leukocyte subpopulations. To address NETs‐mediated HCC metastasis, a peptidic nanomaterial (FTP‐NPs) is developed that specifically binds NE on activated neutrophil membranes and undergoes in situ fibrillar transformation, forming NE‐fibril clusters. These NE‐fibril clusters deactivate NE by altering their conformation or binding mode. Subsequently, a series of feedback mechanisms is triggered, which regulates NE membrane concentration by promoting its transport to the membrane rather than the nucleus. The NE‐fibril clusters can remain on the activated neutrophil membrane for an extended period, enabling continuous binding and deactivation of newly transported NE, thereby reversing the formation of NETs. Besides, the extracellular NE‐fibril clusters also act as a physical barrier to prevent NETs from adhering to tumor cells, further disrupting the metastatic cascade. In vitro, in vivo, and single‐cell RNA sequencing (scRNA‐seq) data confirm that FTP‐NPs significantly reduce NETs formation, reduce metastatic burden, and enhance antitumor immune response. Compared with commercial NE inhibitors, this strategy precisely and locally regulates NE subcellular distribution within neutrophils in tumor tissue, minimizing off‐target effects and systemic toxicity. The NE‐fibril clusters may establish an innovative therapeutic approach for NETs‐mediated tumor metastasis.