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Here, we identified Polygonum cuspidatum-derived nanoparticles (PDNs) as a multifaceted nanotherapeutic that breaks this pathogenic loop. We found that PDNs coencapsulate immediate radical-scavenging metabolites with a functional microRNA, miR5054. Upon endothelial delivery, miR5054 directly targets and silences Keap1 mRNA, leading to sustained activation of the Nrf2 antioxidant pathway. This Nrf2 activation cross-inhibits the pro-inflammatory NF-\u03baB signaling axis in endothelium. The resultant dual amelioration of oxidative and inflammatory stress potently reprograms the wound immune microenvironment, polarizing macrophages toward a pro-healing M2 phenotype. In burn models, PDNs accelerated wound closure, enhanced collagen remodeling, and fostered a Nrf2-high, M2-dominant pro-regenerative niche. The therapeutic effect of PDNs was abolished by a complementary-sequence inhibitor of miR5054, establishing its indispensable role. Furthermore, a synthetic miR5054 mimic recapitulated these benefits, while a thermosensitive hydrogel formulated for PDN delivery enhanced skin penetration and healing efficacy. Our work unveils PDNs as a natural combinatorial therapy that codelivers chemical and genetic components to simultaneously disrupt the oxidative-inflammatory cascade in burns, presenting a translatable, biomimetic strategy for advanced wound management.<\/jats:p>","DOI":"10.1021\/acsnano.6c08834","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:01:57Z","timestamp":1786075317000},"page":"22887-22908","source":"Crossref","is-referenced-by-count":2,"title":["Cross-Kingdom\nmiR5054 Delivery via\n                    <i>Polygonum cuspidatum<\/i>\n                    -Derived Nanoparticles Enhances Burn Wound Healing\nby Regulating Microvascular Environment"],"prefix":"10.1021","volume":"20","author":[{"given":"Qi","family":"Xiu","sequence":"first","affiliation":[{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Guangdong Provincial Clinical Research Center for Laboratory Medicine , , ,","place":["Guangzhou, Guangdong, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-5033","authenticated-orcid":true,"given":"Weilun","family":"Pan","sequence":"additional","affiliation":[{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Guangdong Provincial Clinical Research Center for Laboratory Medicine , , ,","place":["Guangzhou, Guangdong, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Guangdong Provincial Clinical Research Center for Laboratory Medicine , , ,","place":["Guangzhou, Guangdong, P. R. China, 510515"]},{"name":"Fujian Medical University Union Hospital , , ,","place":["Fuzhou, P. R. China, 350001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiling","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Guangdong Provincial Clinical Research Center for Laboratory Medicine , , ,","place":["Guangzhou, Guangdong, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningcen","family":"Li","sequence":"additional","affiliation":[{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Guangdong Provincial Clinical Research Center for Laboratory Medicine , , ,","place":["Guangzhou, Guangdong, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjing","family":"Fan","sequence":"additional","affiliation":[{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Guangdong Provincial Clinical Research Center for Laboratory Medicine , , ,","place":["Guangzhou, Guangdong, P. R. China, 510515"]},{"name":"Zhujiang Hospital, Southern Medical University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510282"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei University of Medicine , , ,","place":["Shiyan, P. R. China, 442000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Feng","sequence":"additional","affiliation":[{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Nanfang Hospital, Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]},{"name":"Guangdong Provincial Clinical Research Center for Laboratory Medicine , , ,","place":["Guangzhou, Guangdong, P. R. 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Vet Surg"},{"issue":"18","key":"2026081810313074900_cit3","doi-asserted-by":"publisher","first-page":"4833","DOI":"10.1016\/j.cell.2024.07.012","article-title":"A systems view of the vascular endothelium in health\nand disease","volume":"187","author":"Augustin","year":"2024","journal-title":"Cell"},{"issue":"2","key":"2026081810313074900_cit4","doi-asserted-by":"publisher","DOI":"10.1002\/INMD.20240062","article-title":"Effects of\nreactive oxygen species and antioxidant strategies on wound healing\nin diabetes","volume":"3","author":"Yu","year":"2025","journal-title":"Interdiscip. Med."},{"issue":"1","key":"2026081810313074900_cit5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.30500\/ivsa.2024.462951.1409","article-title":"Effect of\nLocal Transplantation of Mesenchymal Stem\nCell\/Macrophage Culture Supernatants on Oxidative Stress Markers in\nWound Healing","volume":"20","author":"Mozaffari","year":"2025","journal-title":"Iran J. Vet Surg"},{"issue":"48","key":"2026081810313074900_cit6a","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202403679","article-title":"Kill Two Birds with\nOne Stone: Dual-Metal\nMOF-Nanozyme-Decorated Hydrogels with ROS-Scavenging, Oxygen-Generating,\nand Antibacterial Abilities for Accelerating Infected Diabetic Wound\nHealing","volume":"20","author":"Wei","year":"2024","journal-title":"Small"},{"issue":"4","key":"2026081810313074900_cit6b","doi-asserted-by":"publisher","first-page":"3749","DOI":"10.3390\/ijms24043749","article-title":"Burns: Classification,\nPathophysiology, and Treatment: A Review","volume":"24","author":"Z\u0307wiere\u0142\u0142o","year":"2023","journal-title":"Int.\nJ. Mol. Sci."},{"issue":"6","key":"2026081810313074900_cit7a","doi-asserted-by":"publisher","DOI":"10.1289\/EHP11309","article-title":"Synthetic Phenolic\nAntioxidants and Their Metabolites in Follicular Fluid and Association\nwith Diminished Ovarian Reserve: A Case-Control Study","volume":"131","author":"Hao","year":"2023","journal-title":"Environ. Health Perspect."},{"issue":"51","key":"2026081810313074900_cit7b","doi-asserted-by":"publisher","first-page":"21550","DOI":"10.1021\/acs.est.3c06487","article-title":"Synthetic Antioxidants as Contaminants\nof Emerging Concern in Indoor Environments: Knowns and Unknowns","volume":"57","author":"Ji","year":"2023","journal-title":"Environ. Sci. Technol."},{"issue":"9","key":"2026081810313074900_cit7c","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1038\/s41573-021-00233-1","article-title":"Targeting oxidative stress in disease:\npromise and limitations of antioxidant therapy","volume":"20","author":"Forman","year":"2021","journal-title":"Nat. Rev. Drug Discov"},{"issue":"2","key":"2026081810313074900_cit8a","doi-asserted-by":"publisher","first-page":"281","DOI":"10.4067\/S0716-97602006000200010","article-title":"Antioxidant activity of extract from\nPolygonum aviculare\nL","volume":"39","author":"Hsu","year":"2006","journal-title":"Biol. 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Biotechnol., Biochem."},{"issue":"4","key":"2026081810313074900_cit9","doi-asserted-by":"publisher","DOI":"10.1002\/INMD.20240117","article-title":"Applications\nof bioactive herbal extracts in dressing materials for\nskin wound repair: Ingredients, mechanisms and innovations","volume":"3","author":"Yang","year":"2025","journal-title":"Interdiscip. Med."},{"key":"2026081810313074900_cit10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2024.118079","article-title":"Polygonum\ncuspidatum polysaccharide: A review of its\nextraction and purification, structure analysis, and biological activity","volume":"331","author":"Lai","year":"2024","journal-title":"J. Ethnopharmacol"},{"issue":"24","key":"2026081810313074900_cit11","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202207826","article-title":"Plant-Derived\nVesicle-Like Nanoparticles as Promising Biotherapeutic Tools: Present\nand Future","volume":"35","author":"Feng","year":"2023","journal-title":"Adv. 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