Nanoparticles alter the inflammatory landscape of spinal cord injury and attenuate injury severity

Trauma to the spinal cord results in initial damage to the spinal cord and initiates an inflammatory response that causes secondary damage, which collectively can result in loss of function below the level of the injury. The unbalanced risk-benefit-ratio of methylprednisolone led to our development of nanoparticles that associate with circulating monocytes and neutrophils to reduce inflammation and secondary damage. Herein, we investigate the mechanisms by which NPs directly and indirectly modulate the phenotype and trafficking of monocytes and neutrophils, and how altering the inflammatory cascade leads to mechanisms that promote a regenerative environment. Using adoptive transfer of cells to monitor trafficking, NP treatment reduced the extent of myeloid cell recruitment to the injury, yet did not impact the composition of adoptively transferred monocytes or neutrophils. The proportion of inflammatory monocytes was reduced with nanoparticle treatment, and single cell sequencing analysis indicated increased polarization towards an M2-like phenotype. Sequencing analysis also demonstrated that the outgoing signals from the monocytes and neutrophils influenced the phenotype of numerous cell types, including endothelial cells, fibroblasts, oligodendrocyte progenitor cells, and Schwann cells. This signaling between the cell compartments involves a combination of soluble and matrix signals, with NP treatment enhancing expression of genes associated with anti-inflammatory phenotypes, angiogenesis, neuroprotection, and promotion of axon outgrowth or decreasing expression of inhibitors to regeneration. Collectively, NP delivery leads to direct and indirect effects on monocytes and neutrophils, which subsequently influence gene expression and intercellular signaling networks that promote a growth-permissive environment.