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Current therapeutic strategies failed to simultaneously target lipid deposition, chronic inflammation, and endothelial dysfunction. Herein, we developed BIFD, a conformationally variable peptide targeting lysophosphatidylcholine (LPC) on oxidized low\u2010density lipoproteins (ox\u2010LDL), which binds ox\u2010LDL to form nanoaggregates, blocking ox\u2010LDL toxicity, reducing inflammation, promoting metabolism\/excretion of ox\u2010LDL in macrophage. In addition, both ox\u2010LDL specifically distributed in plaque sites and the targetability of BIFD to ox\u2010LDL enable the BIFD targetability to plaque of AS. Therefore, rapamycin (Rapa), an anti\u2010inflammatory drug, is designed to be encapsulated into BIFD to form Rapa@BIFD nanoparticles (NPs). Rapa@BIFD may target plaque, enhancing accumulation and retention of Rapa@BIFD on the AS lesion. Consequently, Rapa@BIFD demonstrated high efficacy against AS with minimal side effects. In vitro and in vivo studies in apolipoprotein E\u2010knockout murine and canine models revealed that Rapa@BIFD effectively reduced oxidative damage, and inflammatory responses, while promoting lipid metabolism and excretion. Rapa@BIFD mitigated side effects of Rapa, such as hyperlipidemia and splenic toxicity. These findings present a transformative multitarget for AS, combining efficacy with minimal side effects and enhanced clinical translatability.<\/jats:p>","DOI":"10.1002\/adma.202521108","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:28:57Z","timestamp":1778570937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformationally Variable Peptides Trap and Detoxify Ox\u2010LDL in Plaques for Attenuating Atherosclerosis in Multiple Species"],"prefix":"10.1002","volume":"38","author":[{"given":"Hong\u2010Mei","family":"Zhao","sequence":"first","affiliation":[{"name":"Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases Institute of Basic Medical Sciences Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"Research Center of High Altitude Medicine  Xining China"},{"name":"Qinghai Cardio\u2010Cerebrovascular Specialty Hospital Qinghai High Altitude Medical Research Institute  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010Ye","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; 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