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Here, we observed aberrant fibrin accumulation in inflamed periodontal tissues and hypothesized that fibrin acts as a pathogenic mediator that promotes neutrophil recruitment and activation, thereby triggering neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production. To therapeutically target fibrin deposition, we developed a ROS-responsive hydrogel (PVHA@tPA) that enables localized delivery of tissue plasminogen activator (tPA), activating plasminogen to mediate fibrin degradation. In vitro, tPA released from the hydrogel degraded fibrin matrices in the presence of plasminogen, which restrained fibrin-mediated neutrophil adhesion and migration while suppressing subsequent NETs formation and ROS overproduction. By attenuating this neutrophil overactivation, the treatment improved the osteogenic capacity of periodontal ligament stem cells (PDLSCs) and the angiogenic potential of human umbilical vein endothelial cells (HUVECs). In vivo, PVHA@tPA treatment in a mouse periodontitis model reduced gingival fibrin deposition, attenuated neutrophil-associated inflammation, downregulated proinflammatory factors, and alleviated alveolar bone loss. Together, these findings identify fibrin deposition as a key driver of neutrophil dysregulation in periodontitis and establish fibrin-targeted therapy as a promising strategy to rebalance neutrophil responses and ameliorate periodontitis.<\/jats:p>","DOI":"10.1177\/00220345261468280","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T07:39:13Z","timestamp":1788161953000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Fibrin Deposit Alleviates Periodontitis via Neutrophil Modulation"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2595-0012","authenticated-orcid":false,"given":"B.","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Periodontology\/Biomaterials, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University &amp; Shandong Key Laboratory of Oral Diseases &amp; Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration &amp; Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6699-2263","authenticated-orcid":false,"given":"J.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Periodontology\/Biomaterials, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University &amp; Shandong Key Laboratory of Oral Diseases &amp; Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration &amp; Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6822-1569","authenticated-orcid":false,"given":"T.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Periodontology\/Biomaterials, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University &amp; 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