After spinal cord injury (SCI) there is excessive inflammation and extensive infiltration of immune cells that leads to additional neural damage. Interleukin (IL)-4, IL-10, and IL-13 are anti-inflammatories that have been shown to reduce several pro-inflammatory species, alter macrophage state, and provide neuroprotection. However, these anti-inflammatories have a short half-life, do not cross the blood-spinal cord barrier, and large systemic doses of ant-inflammatory cytokines can cause increased susceptibility to infections. In this study, we used mineral coated microparticles (MCMs) to bind, stabilize and deliver biologically active IL-4, IL-10, and IL-13 in a sustained manner directly to the injury site. Rats with a T10 SCI were given an intraspinal injection of cytokine-loaded MCMs 6 h post-injury. Testing of 27 cytokine/chemokine levels 24 h post-injury demonstrated that MCMs delivering IL-4, IL-10, and IL-13 significantly reduced inflammation (P <
0.0002). Rats treated with MCMs+(IL-4, IL-10, IL-13) had significantly higher Basso-Beattie-Bresnahan locomotor rating scores (P = 0.0021), Ladder Rung Test scores (P = 0.0021), and significantly longer latency threshold with the Hargreaves Test (P = 0.0123), compared to Injured Controls. Analyses of post-fixed spinal cords revealed significantly less spinal cord atrophy (P = 0.0344) in rats treated with MCMs+(IL-4, IL-10, IL-13), and diffusion tensor imaging tractography revealed significantly more tracts spanning the injury site (P = 0.0025) in rats treated with MCMs+(IL-4, IL-10, IL-13) compared to Injured Controls. In conclusion, MCMs delivering IL-4, IL-10, and IL-13 significantly reduced inflammation post-SCI, resulting in significantly less spinal cord damage and a significant improvement in hind limb function.