BACKGROUND: Previous investigations have shown that local application of nanoparticles presenting the carbohydrate moiety galactose-a-1,3-galactose (α-gal epitopes) enhance wound healing by activating the complement system and recruiting pro-healing macrophages to the injury site. Our companion in vitro paper suggest α-gal epitopes can similarly recruit and polarize human microglia toward a pro-healing phenotype. In this continuation study, we investigate the in vivo implications of α-gal nanoparticle administration directly to the injured spinal cord. METHODS: α-Gal knock-out (KO) mice subjected to spinal cord crush were injected either with saline (control) or with α-gal nanoparticles immediately following injury. Animals were assessed longitudinally with neurobehavioral and histological endpoints. RESULTS: Mice injected with α-gal nanoparticles showed increased recruitment of anti-inflammatory macrophages to the injection site in conjunction with increased production of anti-inflammatory markers and a reduction in apoptosis. Further, the treated group showed increased axonal infiltration into the lesion, a reduction in reactive astrocyte populations and increased angiogenesis. These results translated into improved sensorimotor metrics versus the control group. CONCLUSIONS Application of α-gal nanoparticles after spinal cord injury (SCI) induces a pro-healing inflammatory response resulting in neuroprotection, improved axonal ingrowth into the lesion and enhanced sensorimotor recovery. The data shows α-gal nanoparticles may be a promising avenue for further study in CNS trauma.GRAPHICAL ABSTRACT Putative mechanism of therapeutic action by α-gal nanoparticles. A. Nanoparticles injected into the injured cord bind to anti-Gal antibodies leaked from ruptured capillaries. The binding of anti-Gal to α-gal epitopes on the α-gal nanoparticles activates the complement system to release complement cleavage chemotactic peptides such as C5a, C3a that recruit macrophages and microglia. These recruited cells bind to the anti-Gal coated α-gal nanoparticles and are further polarized into the M2 state. B. Recruited M2 macrophages and microglia secrete neuroprotective and prohealing factors to promote tissue repair, neovascularization and axonal regeneration (C.).