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Excessive activation of immune cells and damage of reactive oxygen species (ROS) are the main factors that exacerbate lung injury. Here, the multifaceted immunomodulatory nanocomplexes targeting the proinflammatory neutrophilic activation and ROS damage are established. The S100A8\/9 inhibitor, ABR2575, is loaded in the nanocomplexes, which effectively blocks the neutrophils\u2010S100A8\/A9\u2010 toll\u2010like receptors (TLRS)\u2010Inflammasome signaling in ALI. Synergically, the SiH nanosheets are encapsulated together with ABR2575 into the core of poly(lactic\u2010\n                    <jats:italic>co<\/jats:italic>\n                    \u2010glycolic acid) (PLGA) nanosponges, to achieve sustainable hydrogen release for the alleviation of ROS\u2010induced lung tissue injury, and also promote the M2 polarization of macrophages. This novel combination strategy is proven to significantly suppress the infiltration of neutrophils and pro\u2010inflammatory macrophages into the lungs, decrease the activation of neutrophils and pro\u2010inflammatory monocytes in the blood, facilitate the anti\u2010inflammatory polarization of macrophages and monocytes, and reduce the expression of pro\u2010inflammatory cytokines in both the lung and blood circulation, all of which alleviate the lung injuries in preclinical murine ALI models. The current investigations offer a novel nanomedicine for the treatment of ALI with great potential in clinical invention.\n                  <\/jats:p>","DOI":"10.1002\/advs.202411823","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:26:36Z","timestamp":1735629996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Multifaceted Immunomodulatory Nanocomplexes Target Neutrophilic\u2010ROS Inflammation in Acute Lung Injury"],"prefix":"10.1002","volume":"12","author":[{"given":"Fan","family":"Su","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine and Emergency, Shanghai Chest Hospital Shanghai Jiao Tong University  Shanghai 200030 P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Xuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine Tongji University  Shanghai 200072 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1663-5468","authenticated-orcid":false,"given":"Han","family":"Lin","sequence":"additional","affiliation":[{"name":"Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine Tongji University  Shanghai 200072 P. R. China"},{"name":"State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease Chinese Academy of Medical Sciences (2021RU012)  Shanghai 200050 P. R. 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