OBJECTIVE: Spinal cord injury (SCI) leads to severe motor and sensory deficits, with limited treatment options. This study investigates how methylprednisolone-loaded nanoparticles (MP-NPs) modulate SCI repair by targeting solute carrier family 16 member 3 (SLC16A3) and reshaping the macrophage-inflammatory microenvironment. METHODS: Transcriptome data were analyzed to identify differentially expressed genes (DEGs) associated with SCI. Immune infiltration and WGCNA (Weighted Gene Co-expression Network Analysis) identified genes linked to M2 macrophage polarization, pinpointing SLC16A3 as a key regulatory factor. MP-NPs were synthesized, characterized, and tested for their effects on macrophage polarization, neuronal protection, and SCI recovery in rats. RESULTS: We identified 612 DEGs related to inflammation and immune response in SCI. SLC16A3, upregulated in SCI, was downregulated by MP-NPs. In vitro, MP-NPs promoted M2 macrophage polarization, enhanced neuronal survival, and supported neural stem cell differentiation. In vivo, MP-NPs significantly improved motor recovery, reduced inflammation, and facilitated neural repair in SCI rats. CONCLUSION: MP-NPs downregulate SLC16A3 and modulate the macrophage-inflammatory environment, promoting neural repair and functional recovery in SCI, offering a promising therapeutic strategy.