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We performed in vivo experiments with TAR\u2010injected ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice and in vitro co\u2010culture of macrophages with extracellular vesicles (EVs) from TAR\u2010treated endothelial cells (ECs). Single\u2010cell RNA sequencing were used to explore the regulatory effects and molecular pathways of ECs\u2010derived EVs in smoke\u2010related AS. Cigarette TAR significantly stimulated ECs EV secretion and aggravated atherosclerotic plaques, while the EV inhibitor GW4869 alleviated these lesions. RNA\u2010seq indicated TAR facilitated AS by increasing macrophage extracellular traps\u00a0(METs) formation. Combined in vivo and in vitro proteomics showed TDP43 was highly enriched in circulating EVs from smoking patients, TAR\u2010treated mice, and stimulated ECs. TDP43 knockdown alleviated TAR\u2010induced AS, accompanied by suppressed METs and inflammatory responses. Mechanistically, EV\u2010delivered TDP43 bound macrophage VDAC1 to induce mitochondria\u2010associated membranes (MAMs), triggering Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload\/METs; 2\u2010APB and BAPTA blocked this process. Retinoic acid (RA) might bind with TDP43 to inhibit MAMs, thereby reducing METs and mitigating smoke\u2010related AS. Cigarette TAR accelerates ASthrough EC EV\u2010packaged TDP43 partly, which binds VDAC1 to induce MAMs, calcium overload, METs, and inflammation. RA may serve as a putative protective molecule for the progression of smoking\u2010related atherosclerotic plaques.\n                  <\/jats:p>","DOI":"10.1002\/advs.78001","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Vesicle Packaged TDP43 Derived From ECs Exacerbates Cigarette Tar\u2010Related Atherosclerosis Progression via Enhancing Macrophage Extracellular Traps"],"prefix":"10.1002","author":[{"given":"Xinxin","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Cardiology the Second Affiliated Hospital of Harbin Medical University State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD)  Harbin P. R. China"},{"name":"The Key Laboratory of Myocardial Ischemia Chinese Ministry of Education  Harbin P. R. 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