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Adv."],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>\n                    Therapeutic angiogenesis based on gene therapies is a potential peripheral artery disease (PAD) treatment yet needs a more stable, efficient, and high-affinity delivery vector and an optimized delivery strategy. Here, we engineered three-dimensional graphene nanoparticles modified with folic acid and polyethyleneimine for macrophage-specific delivery of interleukin-4 plasmids (pIL-4), forming GNPs-pIL-4 for local intramuscular injection. GNPs-pIL-4 had uniform size, positive surface charge, and strong nucleic acid loading capacity (\n                    <jats:italic toggle=\"yes\">K<\/jats:italic>\n                    <jats:sub>d<\/jats:sub>\n                    : 25\u00a0nanomolar). In vivo, GNPs-pIL-4 reshaped the ischemic microenvironment by inducing reparative M2 macrophage polarization. Mediated by macrophages, GNPs-pIL-4 improved muscle contractility, delayed strength loss, and enhanced blood perfusion and oxygen saturation. Mechanistically, GNPs-pIL-4 specifically turned on the oncostatin M\u2013mediated macrophage-endothelium communication and then activated the angiogenesis, with increased endothelial sprouting, migration, and tube formation. These effects attributed to the down-regulated\n                    <jats:italic toggle=\"yes\">S<\/jats:italic>\n                    -nitrosoglutathione reductase expression, thereby increasing S-nitrosylation at the C209 site of endoglin. GNPs-pIL-4 represents a promising gene therapy strategy for PAD.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed5692","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:01:07Z","timestamp":1786557667000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["GNPs-pIL-4 reprograms macrophage polarization and activates the OSM\/GSNOR\/ENG axis to improve angiogenesis in ischemic limbs"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7042-8000","authenticated-orcid":true,"given":"Peng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Department of Interventional Radiology and Vascular Surgery, Third Hospital, Peking University, Beijing, China."},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China."},{"name":"Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7367-808X","authenticated-orcid":true,"given":"Jinman","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Department of Interventional Radiology and Vascular Surgery, Third Hospital, Peking University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2634-7819","authenticated-orcid":true,"given":"Yizhou","family":"Hao","sequence":"additional","affiliation":[{"name":"Moxi Technology, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2281-3825","authenticated-orcid":true,"given":"Xiangrui","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Department of Interventional Radiology and Vascular Surgery, Third Hospital, Peking University, Beijing, China."},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China."},{"name":"Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6271-9371","authenticated-orcid":true,"given":"Hongbiao","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Department of Interventional Radiology and Vascular Surgery, Third Hospital, Peking University, Beijing, China."},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China."},{"name":"Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5508-6513","authenticated-orcid":true,"given":"Guizimeng","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Department of Interventional Radiology and Vascular Surgery, Third Hospital, Peking University, Beijing, China."},{"name":"Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5217-8139","authenticated-orcid":true,"given":"Peiyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Department of Interventional Radiology and Vascular Surgery, Third Hospital, Peking University, Beijing, China."},{"name":"Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4956-227X","authenticated-orcid":true,"given":"Yuwei","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Department of Interventional Radiology and Vascular Surgery, Third Hospital, Peking University, Beijing, China."},{"name":"Department of Physiology and 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