Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury

Abstract

Traumatic primary spinal cord injury (SCI) results in paralysis below the level of injury and is associated with infiltration of hematogenous innate immune cells into the injured cord. Methylprednisolone has been applied to reduce inflammation following SCI, yet was discontinued due to an unfavorable risk-benefit ratio associated with off-target effects. In this study, i.v. administered poly(lactide-coglycolide) nanoparticles were internalized by circulating monocytes and neutrophils, reprogramming these cells based on their physicochemical properties and not by an active pharmaceutical ingredient, to exhibit altered biodistribution, gene expression, and function. Approximately 80% of nanoparticle-positive immune cells were observed within the injury, and, additionally, the overall accumulation of innate immune cells at the injury was reduced 4-fold, coinciding with down-regulated expression of proinflammatory factors and increased expression of antiinflammatory and proregenerative genes. Furthermore, nanoparticle administration induced macrophage polarization toward proregenerative phenotypes at the injury and markedly reduced both fibrotic and gliotic scarring 3-fold. Moreover, nanoparticle administration with the implanted multichannel bridge led to increased numbers of regenerating axons, increased myelination with about 40% of axons myelinated, and an enhanced locomotor function (score of 6 versus 3 for control group). These data demonstrate that nanoparticles provide a platform that limits acute inflammation and tissue destruction, at a favorable risk-benefit ratio, leading to a proregenerative microenvironment that supports regeneration and functional recovery. These particles may have applications to trauma and potentially other inflammatory diseases.

Biomaterials in Neurodegenerative Disorders: A Promising Therapeutic Approach

“…Park and colleagues reprogrammed circulating monocytes and neutrophils through PLGA nanoparticles. The authors noticed that the treatment caused a downregulated expression of proinflammatory factors and an enhanced expression of anti-inflammatory and pro-regenerative genes, leading to an increased number of regenerating axons, increased myelination, and enhanced locomotor function [98]. In SCI, magnetic nanoparticles were used to track specific cells after implantation [99].…”

Neutrophils preferentially phagocytose elongated particles—An opportunity for selective targeting in acute inflammatory diseases

“…Recently, researchers have introduced biodegradable particles for targeting blood leukocytes as a strategy for the treatment of or to control the severity of many of the inflammatory conditions mentioned above. As an example, biodegradable particles have been used to modulate immune cells to reduce inflammation and disease symp-toms in lupus, spinal cord injury, and sepsis models (4,(15)(16)(17). However, we know little about the specificity of these systems for targeting various leukocyte subpopulations.…”

The role of hepatocyte growth factor in mesenchymal stem cell-induced recovery in spinal cord injured rats

“…Inflammation has been proven to play a critical role in such secondary damage following SCI. After the trauma, several pro-inflammatory cytokines, triggers of post-trauma-induced inflammation, accumulate in the injured lesion, causing the recruitment and activation of inflammatory cells [5,6]. At the same time, the injured lesion is not able to produce a sufficient amount of anti-inflammatory cytokines in comparison to the marked increased in pro-inflammatory cytokines, leading to an inflammatory cytokine imbalance [6,7].…”