Nanoparticle‐Mediated Immunometabolic‐Epigenetic Remodeling Enhances Schwann Cell‐Macrophage Interaction for Sciatic Nerve Regeneration

Peripheral nerve regeneration continues to pose a significant clinical challenge, primarily attributable to the inherently limited regenerative capacity of axons and the intricate inflammatory microenvironment that develops following injury. 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-term local retention and drives coordinated immunometabolic-epigenetic remodeling to promote sciatic nerve regeneration. Through integrated multi-omics analyses, we identify a previously unrecognized S100a4⁺ macrophage substate, which is epigenetically activated via PW-induced accumulation of α-ketoglutarate and subsequent Kdm4a/b-mediated demethylation of the repressive histone mark H3K9me3 at the S100a4 gene locus. Furthermore, these reprogrammed macrophages secrete itaconate, a previously unidentified neuro-immune mediator, which effectively supports Schwann cell proliferation under inflammatory stress. This nanoparticle-enabled metabolic-epigenetic 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-mediated cell reprogramming via coordinated immunometabolic-epigenetic remodeling, offering a versatile and translatable strategy with broad potential for treating neurodegenerative disorders.