{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T16:13:34Z","timestamp":1786637614712,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573345"],"award-info":[{"award-number":["82573345"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82502346"],"award-info":[{"award-number":["82502346"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Atherosclerosis remains the leading cause of cardiovascular mortality, with elevated oxidized low\u2010density lipoprotein (oxLDL) as a key driver. oxLDL metabolism involves two critical steps: generation mediated by proprotein convertase subtilisin\/kexin type 9 (PCSK9)\u2010induced LDLR degradation, and plaque uptake via lectin\u2010like oxLDL receptor\u20101 (LOX\u20101). Current PCSK9 inhibitors reduce oxLDL production but show limited effects on plaque oxLDL uptake and inflammation. Thus, synergistic strategies targeting both steps are urgently needed. To address this, we developed a hepatic\u2010plaque targeting nanoparticle, siPCSK9@PEAL NPs\u2010aL, based on a PEG\u2010PLGA\u2010PLL framework. The nanoparticle was surface\u2010functionalized with anti\u2010LOX\u20101 antibody for plaque targeting. Concurrently, optimized particle size enabled hepatic accumulation while minimizing clearance by the reticuloendothelial system (RES), facilitating effective hepatic delivery of siPCSK9. The PLGA core allowed controlled siRNA release, and the cationic PLL layer promoted efficient condensation and protection. In vitro, this system effectively silenced PCSK9, downregulated LOX\u20101, rescued mitochondrial function and reduced apoptosis. In advanced atherosclerosis mice, weekly administration significantly reduced aortic plaque burden, stabilized plaque composition, and normalized serum lipid levels. Lipidomics showed oxLDL\u2010associated lipid downregulation and metabolic networks remodeling. Taken together, this dual\u2010targeting nanodrug integrates systemic lipid\u2010lowering with local anti\u2010inflammatory effects by simultaneously inhibiting oxLDL generation and utilization, offering a promising precision therapeutic strategy for atherosclerosis.<\/jats:p>","DOI":"10.1002\/advs.77100","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T15:16:02Z","timestamp":1786634162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plaque\u2010Hepatic Targeting Nanotherapy Disrupts the PCSK9\u2010LOX\u20101 Axis to Suppress oxLDL in Atherosclerosis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3609-0271","authenticated-orcid":false,"given":"Yi","family":"Duan","sequence":"first","affiliation":[{"name":"Department of Ultrasound Xinhua Hospital School of Medicine Shanghai Jiao Tong University Shanghai China"},{"name":"State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8837-6074","authenticated-orcid":false,"given":"Yijie","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Xinhua Hospital School of Medicine Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9593-176X","authenticated-orcid":false,"given":"Jiangtao","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3781-7845","authenticated-orcid":false,"given":"Yourong","family":"Duan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3694-5826","authenticated-orcid":false,"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0212-1477","authenticated-orcid":false,"given":"Yi","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Xinhua Hospital School of Medicine Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease and Stroke Statistics\u20142021 Update","volume":"143","author":"Virani S. 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