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While immunometabolic modulation has emerged as a promising therapeutic avenue, achieving precise and sustained intervention within the injury microenvironment remains technically challenging. Here, we introduce a biomimetic Prussian White nanoparticle (PW) that facilitates long\u2010term local retention and drives coordinated immunometabolic\u2010epigenetic remodeling to promote sciatic nerve regeneration. Through integrated multi\u2010omics analyses, we identify a previously unrecognized S100a4\n                    <jats:sup>+<\/jats:sup>\n                    macrophage substate, which is epigenetically activated via PW\u2010induced accumulation of \u03b1\u2010ketoglutarate and subsequent Kdm4a\/b\u2010mediated demethylation of the repressive histone mark H3K9me3 at the S100a4 gene locus. Furthermore, these reprogrammed macrophages secrete itaconate, a previously unidentified neuro\u2010immune mediator, which effectively supports Schwann cell proliferation under inflammatory stress. This nanoparticle\u2010enabled metabolic\u2010epigenetic dialogue between macrophages and Schwann cells markedly enhances functional and structural recovery in both rodent and canine models of sciatic nerve injury. Our findings establish a paradigm of material\u2010mediated cell reprogramming via coordinated immunometabolic\u2010epigenetic remodeling, offering a versatile and translatable strategy with broad potential for treating neurodegenerative disorders.\n                  <\/jats:p>","DOI":"10.1002\/advs.202522093","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T11:32:19Z","timestamp":1771587139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nanoparticle\u2010Mediated Immunometabolic\u2010Epigenetic Remodeling Enhances Schwann Cell\u2010Macrophage Interaction for Sciatic Nerve Regeneration"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenying","family":"Xu","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Neuro\u2010Ultrasound for Diagnosis and Treatment Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of 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