Neutrophil Decoys with Anti‐Inflammatory and Anti‐Oxidative Properties Reduce Secondary Spinal Cord Injury and Improve Neurological Functional Recovery

Following spinal cord injury (SCI), immune cell infiltration creates an inflammatory and oxidative microenvironment (known as the secondary injury), which causes neuron death and spinal cord damage, and dramatically hinders neurological functional recovery. Strategies that inhibit the infiltration and/or function of neutrophils offer promises for SCI treatment because they can reduce the secondary injury; however, such strategies remain largely unexplored. Herein, a strategy using neutrophil membrane‐coated nanoparticles (NPs) as decoys (neutrophil decoy, ND) is presented to reduce local neutrophil infiltration and relieve oxidative stress in the injured spinal cord after SCI. Coated with membranes of activated neutrophils, the NDs inherit multiple receptors from the “parent” neutrophils, which can adsorb and neutralize the elevated neutrophil‐related cytokines. In addition, polydopamine NPs with multi‐antioxidative properties (selected as the core for ND) scavenge excessive reactive oxygen and nitrogen species. In a contusion model of SCI, ND treatment significantly reduces neutrophil infiltration and reprograms the inflammatory and oxidative microenvironment in injured spinal cords. Importantly, ND treatment significantly improves neural regeneration and functional recovery in rats. Such a nano‐decoy platform opens up new approaches for efficiently treating SCI.

[1]  N. Terrando,et al.  Neuroinflammation after surgery: from mechanisms to therapeutic targets , 2020, Nature Immunology.

[2]  F. Quintana,et al.  The Role of Astrocytes in CNS Inflammation. , 2020, Trends in immunology.

[3]  Yun‐Xia Sun,et al.  Recent Advances of Cell Membrane‐Coated Nanomaterials for Biomedical Applications , 2020, Advanced Functional Materials.

[4]  B. Rothen‐Rutishauser,et al.  From Bioinspired Glue to Medicine: Polydopamine as a Biomedical Material , 2020, Materials.

[5]  S. Barnett,et al.  Multi-target approaches to CNS repair: olfactory mucosa-derived cells and heparan sulfates , 2020, Nature Reviews Neurology.

[6]  A. Mócsai,et al.  Neutrophils as emerging therapeutic targets , 2020, Nature Reviews Drug Discovery.

[7]  W. Young,et al.  Clinical Neurorestorative Therapeutic Guidelines for Spinal Cord Injury (IANR/CANR version 2019) , 2019, Journal of orthopaedic translation.

[8]  V. Labhasetwar,et al.  Nanoparticles with antioxidant enzymes protect injured spinal cord from neuronal cell apoptosis by attenuating mitochondrial dysfunction. , 2019, Journal of controlled release : official journal of the Controlled Release Society.

[9]  Yucai Wang,et al.  Pseudo-Neutrophil Cytokine Sponges Disrupt Myeloid Expansion and Tumor Trafficking to Improve Cancer Immunotherapy. , 2019, Nano letters.

[10]  W. Qu,et al.  Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice , 2019, Nature Communications.

[11]  Y. Tachibana,et al.  Dual microglia effects on blood brain barrier permeability induced by systemic inflammation , 2019, Nature Communications.

[12]  Emily B. Ehlerding,et al.  Intrathecal Administration of Nanoclusters for Protecting Neurons against Oxidative Stress in Cerebral Ischemia/Reperfusion Injury. , 2019, ACS nano.

[13]  Emily B. Ehlerding,et al.  A Melanin‐Based Natural Antioxidant Defense Nanosystem for Theranostic Application in Acute Kidney Injury , 2019, Advanced functional materials.

[14]  B. Liu,et al.  High-dose methylprednisolone for acute traumatic spinal cord injury , 2019, Neurology.

[15]  Brian J Cummings,et al.  Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury , 2019, Proceedings of the National Academy of Sciences.

[16]  A. Ivetic,et al.  L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling , 2019, Front. Immunol..

[17]  Faith H. Brennan,et al.  Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2. , 2019, JCI insight.

[18]  Yongzhong Du,et al.  Polysialic-Acid-Based Micelles Promote Neural Regeneration in Spinal Cord Injury Therapy. , 2019, Nano letters.

[19]  Ronnie H. Fang,et al.  Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis , 2018, Nature Nanotechnology.

[20]  Xingzhong Zhao,et al.  Platelet–Leukocyte Hybrid Membrane‐Coated Immunomagnetic Beads for Highly Efficient and Highly Specific Isolation of Circulating Tumor Cells , 2018, Advanced Functional Materials.

[21]  P. Weinstein,et al.  Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis , 2018, eNeuro.

[22]  Brian J Cummings,et al.  Local Immunomodulation with Anti-inflammatory Cytokine-Encoding Lentivirus Enhances Functional Recovery after Spinal Cord Injury. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[23]  Ronnie H. Fang,et al.  Cell Membrane Coating Nanotechnology , 2018, Advanced materials.

[24]  José Zariffa,et al.  Rehabilitation technologies and interventions for individuals with spinal cord injury: translational potential of current trends , 2018, Journal of NeuroEngineering and Rehabilitation.

[25]  S. Kirshblum,et al.  Clinical Trials in Traumatic Spinal Cord Injury , 2018, Neurotherapeutics.

[26]  C. Zhang,et al.  Neutrophil‐Based Drug Delivery Systems , 2018, Advanced materials.

[27]  J. Silver,et al.  The Biology of Regeneration Failure and Success After Spinal Cord Injury. , 2018, Physiological reviews.

[28]  R. Langer,et al.  Nanoparticulate Drug Delivery Systems Targeting Inflammation for Treatment of Inflammatory Bowel Disease. , 2017, Nano today.

[29]  A. Lakatos,et al.  Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair , 2017, The Journal of Neuroscience.

[30]  M. Whalen,et al.  Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift , 2017, Neuron.

[31]  K. Leong,et al.  Functional Recovery of Contused Spinal Cord in Rat with the Injection of Optimal‐Dosed Cerium Oxide Nanoparticles , 2017, Advanced science.

[32]  B. Barres,et al.  Reactive Astrocytes: Production, Function, and Therapeutic Potential. , 2017, Immunity.

[33]  A. Curt,et al.  Traumatic spinal cord injury , 2017, Nature Reviews Disease Primers.

[34]  A. Ropper,et al.  Acute Spinal Cord Compression , 2017, The New England journal of medicine.

[35]  Hülya Bayır,et al.  The far-reaching scope of neuroinflammation after traumatic brain injury , 2017, Nature Reviews Neurology.

[36]  R. Du,et al.  Comprehensive Insights into the Multi-Antioxidative Mechanisms of Melanin Nanoparticles and Their Application To Protect Brain from Injury in Ischemic Stroke. , 2017, Journal of the American Chemical Society.

[37]  A. Roberts,et al.  Targeting GM-CSF in inflammatory diseases , 2016, Nature Reviews Rheumatology.

[38]  M. Tessier-Lavigne,et al.  Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx , 2015, The Journal of Neuroscience.

[39]  D. Eiferman,et al.  Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury , 2015, Trends in Neurosciences.

[40]  A. Luster,et al.  The role of tissue resident cells in neutrophil recruitment. , 2015, Trends in immunology.

[41]  R. Ransohoff,et al.  Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. , 2015, Trends in pharmacological sciences.

[42]  James T. Walsh,et al.  Dealing with Danger in the CNS: The Response of the Immune System to Injury , 2015, Neuron.

[43]  B. Brown,et al.  Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury , 2014, Nature.

[44]  J. Lord,et al.  The systemic immune response to trauma: an overview of pathophysiology and treatment , 2014, The Lancet.

[45]  A. Salgado,et al.  From basics to clinical: A comprehensive review on spinal cord injury , 2014, Progress in Neurobiology.

[46]  S. Reddy,et al.  Reactive oxygen species in inflammation and tissue injury. , 2014, Antioxidants & redox signaling.

[47]  C. Hulsebosch,et al.  Reactive oxygen species contribute to neuropathic pain and locomotor dysfunction via activation of CamKII in remote segments following spinal cord contusion injury in rats , 2013, PAIN®.

[48]  Lehui Lu,et al.  Dopamine‐Melanin Colloidal Nanospheres: An Efficient Near‐Infrared Photothermal Therapeutic Agent for In Vivo Cancer Therapy , 2013, Advanced materials.

[49]  P. Kubes,et al.  Neutrophil recruitment and function in health and inflammation , 2013, Nature Reviews Immunology.

[50]  R. Ransohoff,et al.  Inflammatory cell trafficking across the blood–brain barrier: chemokine regulation and in vitro models , 2012, Immunological reviews.

[51]  H. Zhu,et al.  Oxidative stress in spinal cord injury and antioxidant-based intervention , 2011, Spinal Cord.

[52]  Balaraman Kalyanaraman,et al.  Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. , 2012, Free radical biology & medicine.

[53]  J. Flemming,et al.  Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury , 2011, Spinal Cord.

[54]  M. Simon,et al.  NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain , 2010, Proceedings of the National Academy of Sciences.

[55]  Janet S. Lee,et al.  CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection. , 2010, Immunity.

[56]  D. Radzioch,et al.  Beneficial effects of secretory leukocyte protease inhibitor after spinal cord injury. , 2010, Brain : a journal of neurology.

[57]  D. McTigue,et al.  Damage control in the nervous system: beware the immune system in spinal cord injury , 2009, Nature Medicine.

[58]  Michal Schwartz,et al.  The bright side of the glial scar in CNS repair , 2009, Nature Reviews Neuroscience.

[59]  P. Kubes,et al.  Depletion of Ly6G/Gr-1 Leukocytes after Spinal Cord Injury in Mice Alters Wound Healing and Worsens Neurological Outcome , 2009, The Journal of Neuroscience.

[60]  S. Christie,et al.  Duration of lipid peroxidation after acute spinal cord injury in rats and the effect of methylprednisolone. , 2008, Neurosurgical focus.

[61]  Christina Chan,et al.  Primary Neuron/Astrocyte Co‐Culture on Polyelectrolyte Multilayer Films: A Template for Studying Astrocyte‐Mediated Oxidative Stress in Neurons , 2008, Advanced functional materials.

[62]  David A Ramsay,et al.  The cellular inflammatory response in human spinal cords after injury. , 2006, Brain : a journal of neurology.

[63]  Fred H. Gage,et al.  Therapeutic interventions after spinal cord injury , 2006, Nature Reviews Neuroscience.

[64]  P. Brookes,et al.  Calcium, ATP, and ROS: a mitochondrial love-hate triangle. , 2004, American journal of physiology. Cell physiology.

[65]  Denis Gris,et al.  Transient Blockade of the CD11d/CD18 Integrin Reduces Secondary Damage after Spinal Cord Injury, Improving Sensory, Autonomic, and Motor Function , 2004, The Journal of Neuroscience.

[66]  A. Zlotnik,et al.  Chemokines: a new classification system and their role in immunity. , 2000, Immunity.

[67]  D. Basso,et al.  A sensitive and reliable locomotor rating scale for open field testing in rats. , 1995, Journal of neurotrauma.