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The alteration of the subcellular localization of neutrophil elastase (NE) is crucial for NETs formation. The majority of NE (\u224880%) 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\u2010mediated HCC metastasis, a peptidic nanomaterial (FTP\u2010NPs) is developed that specifically binds NE on activated neutrophil membranes and undergoes in situ fibrillar transformation, forming NE\u2010fibril clusters. These NE\u2010fibril 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\u2010fibril 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\u2010fibril 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\u2010cell RNA sequencing (scRNA\u2010seq) data confirm that FTP\u2010NPs 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\u2010target effects and systemic toxicity. The NE\u2010fibril clusters may establish an innovative therapeutic approach for NETs\u2010mediated tumor metastasis.<\/jats:p>","DOI":"10.1002\/advs.202517415","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T13:22:27Z","timestamp":1761312147000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In Situ Assembly of Transformable Monopeptide on Activated Neutrophils Attenuates NETs\u2010Induced Hepatocellular Carcinoma Metastasis by Disrupting NE Nuclear Translocation"],"prefix":"10.1002","volume":"13","author":[{"given":"Yichi","family":"Chen","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Advanced Biomaterials Department of Biomedical Engineering Southern University of Science and Technology  Shenzhen 518055 China"},{"name":"Department of Ultrasound Harbin Medical University Cancer Hospital Harbin 150081 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Advanced Biomaterials Department of Biomedical Engineering Southern University of Science and Technology  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Harbin Medical University Cancer Hospital Harbin 150081 China"},{"name":"Heilongjiang Province Key Laboratory of Research on Molecular Targeted Anti\u2010Tumor Drugs Harbin 150081 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayue","family":"Qiu","sequence":"additional","affiliation":[{"name":"Faculty of Chinese Medicine &amp; 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