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This study identifies the transcription factor BMAL1 in alveolar macrophages (AMs) as a key therapeutic target. Mechanistically, BMAL1 represses the expression of the glycolytic enzyme PFKFB3 by binding to the\n                    <jats:italic>Pfkfb3<\/jats:italic>\n                    promoter, thereby inhibiting glycolysis, M1 polarization of AMs, and the generation of pro\u2010inflammatory cytokines and reactive oxygen species (ROS). Based on this regulatory mechanism, a biomimetic nanoplatform, RM@TNT, is engineered for precise SA\u2010ARDS therapy. Fabricated by hybridizing AM membrane\u2010derived nanovesicles with ROS\u2010responsive liposomes, the nanoplatform encapsulates tetrahedral DNA nanostructures (TNT) preloaded with nobiletin (Nob, a BMAL1 agonist) and Tuftsin (an AM\u2010targeting peptide). Following inhalation, the AM membrane tropism of RM@TNT ensures prolonged pulmonary retention, prompting targeted TNT release within the ROS\u2010rich pathological microenvironment. Tuftsin then precisely delivers TNT to AMs, where Nob is intracellularly released to activate BMAL1. This activation upregulates the BMAL1\/PFKFB3 axis, suppressing AM glycolysis, inflammation, and oxidative stress. Treatment with RM@TNT resulted in significantly attenuated lung inflammation, injury, and edema, along with markedly improved survival in SA\u2010ARDS mice. Collectively, this multimodal, targeted metabolic reprogramming approach is a highly promising therapeutic strategy for SA\u2010ARDS.\n                  <\/jats:p>","DOI":"10.1002\/advs.202523782","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T11:04:52Z","timestamp":1776683092000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tetrahedral DNA Nanostructure\u2010Based Biomimetic Nanovesicles Attenuate Sepsis\u2010Associated ARDS by Suppressing Glycolysis via the BMAL1\/PFKFB3 Axis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0944-2342","authenticated-orcid":false,"given":"Yunlong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine &amp; Department of Emergency Renmin Hospital of Wuhan University  Wuhan Hubei 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