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

Jonghyuck Park, Yining Zhang, Eiji Saito, Steve J. Gurczynski, Bethany B. Moore, Brian J. Cummings, Aileen J. Anderson, Lonnie D. Shea

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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.

Original languageEnglish
Pages (from-to)14947-14954
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number30
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. This study was supported by NIH Grants R01EB005678 and R01EB013198. We thank the Unit for Laboratory Animal Medicine at University of Michigan for animal care and maintenance.

Funding Information:
This study was supported by NIH Grants R01EB005678 and R01EB013198. We thank the Unit for Laboratory Animal Medicine at University of Michigan for animal care and maintenance.

Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.

Keywords

  • Immunoengineering
  • Nanomedicine
  • Nerve regeneration
  • Spinal cord injury

ASJC Scopus subject areas

  • General

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