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

ABSTRACT 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.