Macrophage-targeted <i>Mms6</i> mRNA-lipid nanoparticles promote locomotor functional recovery after traumatic spinal cord injury in mice

Traumatic spinal cord injury (SCI) causes severe central nervous system damage. M2 macrophages within the lesion are crucial for SCI recovery. Our previous research revealed that M2 macrophages transfected with magnetotactic bacteria-derived <i>Mms6</i> gene can resist ferroptosis and enhance SCI recovery. To address the limitations of M2 macrophage transplantation, we developed lipid nanoparticles (LNPs) encapsulating <i>Mms6</i> mRNA targeting macrophages (<i>Mms6</i> mRNA-PS/LNPs). The targeting efficiency and therapeutic effect of these LNPs in SCI mice were evaluated. Intravenous administration of <i>Mms6</i> mRNA-PS/LNPs delivered more <i>Mms6</i> mRNAs to lesion-site macrophages than those in the <i>Mms6</i> mRNA-LNP group, which resulted in enhancing motor function recovery, reducing lesion area and scar formation, and promoting neuronal survival and nerve fiber repair. These effects were nullified when macrophages were depleted. These findings suggest that macrophage-targeted delivery of <i>Mms6</i> mRNA is a promising therapeutic strategy for promoting spinal cord repair and motor function recovery in patients with traumatic SCI.