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Plaque\u2010targeted drug delivery to achieve promoted treatment remains the main challenge because of the systemic occurrence of atheroma. Herein, a rapamycin (RAP) spherical nucleic acid (SNA) structure, capable of specifically accumulating in plaques for synergistic atherosclerosis treatment is constructed. By designing consecutive phosphorothioate (PS) at 3\u2019 terminus of the deoxyribonucleic acid (DNA) strand, multiple hydrophobic RAPs are covalently grafted onto the PS segment to form an amphiphilic drug\u2010grafted DNA (RAP\u2010DNA), which successively self\u2010assembles into micellar SNA (RAP\u2010SNA). Moreover, the phosphodiester\u2010DNA segment constitutes the outer shell of RAP\u2010SNA, enabling further hybridization with functional siRNA (targeting lectin\u2010like oxidized low\u2010density lipoprotein receptor\u20101, LOX\u20101) to obtain the drug codelivered SNA (LOX\u20101\/RAP\u2010SNA). With two active ingredients inside, LOX\u20101\/RAP\u2010SNA can not only induce robust autophagy and decrease the evil apoptosis of the pathological macrophages, but also simultaneously prohibit the LOX\u20101\u2010mediated formation of damageable foam cells, realizing the effect of synergistic therapy. As a result, the LOX\u20101\/RAP\u2010SNA significantly reduces the progression of atheroma and stabilizes the plaques, providing a new strategy for synergistically targeted atherosclerosis treatment.<\/jats:p>","DOI":"10.1002\/advs.202105875","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T08:34:58Z","timestamp":1648456498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Plaque\u2010Targeted Rapamycin Spherical Nucleic Acids for Synergistic Atherosclerosis Treatment"],"prefix":"10.1002","volume":"9","author":[{"given":"Yuanyuan","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Radiology Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Jiao Tong University School of Medicine  600 Yi Shan Road Shanghai 200233 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