{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:08:11Z","timestamp":1790075291398,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,18]]},"group-title":"Molecular Biology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Institutes of Health","award":["R56HL173828"],"award-info":[{"award-number":["R56HL173828"]}]},{"name":"Arizona Biomedical Research Centre grant","award":["RFGA2024-022-029"],"award-info":[{"award-number":["RFGA2024-022-029"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Despite advances in lipid-lowering and anti-inflammatory therapies, pharmacological strategies that act directly within established atherosclerotic lesions to suppress plaque progression remain limited. We recently developed a monocyte-mimetic nanoparticle (MoNP) platform that selectively targets inflamed endothelium and delivers Verteporfin (VP), termed MoNP-VP, to suppress YAP\/TAZ-associated endothelial activation and plaque development. Here, we extend this biomimetic nanotherapy by defining the pharmacological effects of MoNP-VP within atherosclerotic vessels and evaluating its therapeutic efficacy in pre-existing plaques under distinct lipid burden.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>MoNP-VP were formulated by encapsulating VP in polymeric cores followed by cloaking with mouse monocyte membranes. Partial ligation was performed in ApoE-deficient mice, and single-cell RNA sequencing was used to define pharmacodynamic responses in carotid lesions. Proprotein convertase subtilisin\/kexin type 9 (PCSK9) gain-of-function was induced in wild-type mice to generate pre-existing aortic lesions, followed by continued high-fat-diet or switching to chow to evaluate MoNP-VP efficacy under persistent hyperlipidemia and lipid-lowering conditions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Single-cell analysis revealed that MoNP-VP remodeled the plaque microenvironment in carotid arteries, selectively reducing foamy macrophage populations while enriching vascular stromal populations associated with fibrotic remodeling. In mice with pre-existing aortic plaques, MoNP-VP suppressed lesion progression and reduced macrophage content under persistent hyperlipidemia. Following diet-induced lipid lowering, MoNP-VP further reduced macrophage accumulation despite no significant change in plaque size. Across both settings, MoNP-VP increased fibroblast-like cell populations and collagen deposition accompanied by activation of TGF\u03b2 signaling, features consistent with a more stable plaque. Importantly, repeated MoNP-VP administration was well tolerated and elicited no overt systemic toxicity.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These findings bridge mechanistic insight and therapeutic efficacy in pre-established plaques by demonstrating that MoNP-VP remodels the inflammatory plaque microenvironment and promotes lesion stabilization, supporting its translational potential as a precision nanotherapy for atherosclerosis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.16.750992","type":"posted-content","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T10:35:43Z","timestamp":1789727743000},"source":"Crossref","is-referenced-by-count":0,"title":["Monocyte-Mimetic Nanoparticle Delivery of Verteporfin Promotes Plaque-Stabilizing Remodeling in Atherosclerosis"],"prefix":"10.64898","author":[{"given":"Ting-Yun","family":"Wang","sequence":"first","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University, Tempe, USA"},{"name":"School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Zehnder","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University, Tempe, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sin-Pei","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University, Tempe, USA"},{"name":"School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Chun","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University, Tempe, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3273-5717","authenticated-orcid":false,"given":"Christopher L.","family":"Plaisier","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University, Tempe, USA"},{"name":"John Shufeldt School of Medicine and Medical Engineering, Arizona State University, Tempe, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuei-Chun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering, Arizona State University, Tempe, USA"},{"name":"John Shufeldt School of Medicine and Medical Engineering, Arizona State University, Tempe, 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