There is an increasing need to develop improved and non-invasive strategies to treat spinal cord injury (SCI). Nanoparticles (NPs) are an enabling technology to improve drug delivery, modulate inflammatory responses, and restore functional responses following SCI. However, the complex pathophysiology associated with SCI presents several distinct challenges that must be overcome for sufficient NP drug delivery to the spinal cord. The objective of this mini-review is to highlight the physiological challenges and cell types available for modulation and discuss several promising advancements using NPs to improve SCI treatment. We will focus our discussion on recent innovative approaches in NP drug delivery and how the implementation of multifactorial approaches to address the proinflammatory and complex immune dysfunction in SCI offers significant potential to improve outcomes in SCI.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
National Spinal Cord Injury Statistical Center, Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, 2018.
Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A, et al. Traumatic spinal cord injury. Nat Rev Dis Primers. 2017;33(1):1–21.
Dumont CM, Margul DJ, Shea LD. Tissue engineering approaches to modulate the inflammatory milieu following spinal cord injury. Cells Tissues Organs. 2016;202:52–66.
Fouad K, Krajacic A, Tetzlaff W. Spinal cord injury and plasticity: opportunities and challenges. Brain Res Bull. 2011;84:337–42.
Saraiva C, Praca C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanoparticle-mediated brain drug delivery: overcoming blood-brain barrier to treat neurodegenerative diseases. J Control Release. 2016;235:34–47.
Kwon BK, Okon E, Hillyer J, Mann C, Baptiste D, Weaver LC, et al. A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma. 2011;28:1545–88.
Song YH, Agrawal NK, Griffin JM, Schmidt CE. Recent advances in nanotherapeutic strategies for spinal cord injury repair. Adv Drug Deliv Rev. 2019;148:38–59.
Zuidema JM, Gilbert RJ, Osterhout DJ. Nanoparticle technologies in the spinal cord. Cells Tissues Organs. 2016;202:102–15.
Zhang MH, Slaby EM, Stephanie G, Yu C, Watts DM, Liu H, et al. Lipid-mediated insertion of toll-like receptor (TLR) ligands for facile immune cell engineering. Front Immunol. 2020;11:560.
Liu H, Moynihan KD, Zheng Y, Szeto GL, Li AV, Huang B, et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature. 2014;507:519–22.
Biscans A, Coles A, Haraszti R, Echeverria D, Hassler M, Osborn M, et al. Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo. Nucleic Acids Res. 2019;47:1082–96.
Osborn MF, Coles AH, Biscans A, Haraszti RA, Roux L, Davis S, et al. Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways. Nucleic Acids Res. 2019;47:1070–81.
Casey LM, Kakade S, Decker JT, Rose JA, Deans K, Shea LD, et al. Cargo-less nanoparticles program innate immune cell responses to toll-like receptor activation. Biomaterials. 2019;218:119333.
Correa S, Boehnke N, Barberio AE, Deiss-Yehiely E, Shi A, Oberlton B, et al. Tuning nanoparticle interactions with ovarian cancer through layer-by-layer modification of surface chemistry. ACS Nano. 2020;14:2224–37.
Gammon JM, Jewell CM. Engineering immune tolerance with biomaterials. Adv Healthc Mater. 2019;8(4):e1801419.
Gomes AC, Mohsen M, Bachmann MF. Harnessing nanoparticles for immunomodulation and vaccines. Vaccines (Basel). 2017;5(1):6.
Evans BC, Fletcher RB, Kilchrist KV, Dailing EA, Mukalel AJ, Colazo JM, et al. An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles. Nat Commun. 2019;10:5012.
Ziemba AM, Gilbert RJ. Biomaterials for local, controlled drug delivery to the injured spinal cord. Front Pharmacol. 2017;8:245.
Lasola JJM, Kamdem H, McDaniel MW, Pearson RM. Biomaterial-driven immunomodulation: cell biology-based strategies to mitigate severe inflammation and sepsis. Front Immunol. 2020;11:1726.
Fontana F, Figueiredo P, Bauleth-Ramos T, Correia A, Santos HA. Immunostimulation and immunosuppression: nanotechnology on the brink. Small Methods. 2018;2:1700347.
Ifergan I, Miller SD. Potential for targeting myeloid cells in controlling CNS inflammation. Front Immunol. 2020;11:571897.
Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99:28–51.
Calvo P, Gouritin B, Villarroya H, Eclancher F, Giannavola C, Klein C, et al. Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat. Eur J Neurosci. 2002;15:1317–26.
Figley SA, Khosravi R, Legasto JM, Tseng YF, Fehlings MG. Characterization of vascular disruption and blood-spinal cord barrier permeability following traumatic spinal cord injury. J Neurotrauma. 2014;31:541–52.
Park J, Zhang Y, Saito E, Gurczynski SJ, Moore BB, Cummings BJ, et al. Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury. Proc Natl Acad Sci U S A. 2019;116:14947–54.
Jeong SJ, Cooper JG, Ifergan I, McGuire TL, Xu D, Hunter Z, et al. Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice. Neurobiol Dis. 2017;108:73–82.
Brown JA, Faley SL, Shi Y, Hillgren KM, Sawada GA, Baker TK, et al. Advances in blood-brain barrier modeling in microphysiological systems highlight critical differences in opioid transport due to cortisol exposure. Fluids Barriers CNS. 2020;17:38.
Surnar B, Basu U, Banik B, Ahmad A, Marples B, Kolishetti N, et al. Nanotechnology-mediated crossing of two impermeable membranes to modulate the stars of the neurovascular unit for neuroprotection. Proc Natl Acad Sci. 2018;115:E12333.
Gonzalez-Carter D, Liu X, Tockary TA, Dirisala A, Toh K, Anraku Y, et al. Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium. Proc Natl Acad Sci U S A. 2020;117:19141–50.
Cerqueira SR, Ayad NG, Lee JK. Neuroinflammation treatment via targeted delivery of nanoparticles. Front Cell Neurosci. 2020;14:576037.
Yun X, Maximov VD, Yu J, Zhu H, Vertegel AA, Kindy MS. Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury. J Cereb Blood Flow Metab. 2013;33:583–92.
Pearson RM, Juettner V, Hong S. Biomolecular corona on nanoparticles: a survey of recent literature and its implications in targeted drug delivery. Front Chem. 2014;2. https://doi.org/10.3389/fchem.2014.00108.
Pearson RM, Hsu H-j, Bugno J, Hong S. Understanding nano-bio interactions to improve nanocarriers for drug delivery. MRS Bull. 2014;39:227–37.
Siebert JR, Conta Steencken A, Osterhout DJ. Chondroitin sulfate proteoglycans in the nervous system: inhibitors to repair. Biomed Res Int. 2014;2014:845323.
Mann AP, Scodeller P, Hussain S, Joo J, Kwon E, Braun GB, et al. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries. Nat Commun. 2016;7:11980.
Sun G, Zeng S, Liu X, Shi H, Zhang R, Wang B, et al. Synthesis and characterization of a silica-based drug delivery system for spinal cord injury therapy. Nano-Micro Lett. 2019;11:23.
Jiang Z, Guan J, Qian J, Zhan C. Peptide ligand-mediated targeted drug delivery of nanomedicines. Biomater Sci. 2019;7:461–71.
Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008;209:378–88.
Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39:3–18.
Papa S, Ferrari R, De Paola M, Rossi F, Mariani A, Caron I, et al. Polymeric nanoparticle system to target activated microglia/macrophages in spinal cord injury. J Control Release. 2014;174:15–26.
Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5:146–56.
Chung W-S, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504:394–400.
Nguyen KB, Pender MP. Phagocytosis of apoptotic lymphocytes by oligodendrocytes in experimental autoimmune encephalomyelitis. Acta Neuropathol. 1997;95:40–6.
Scheib JL, Höke A. An attenuated immune response by Schwann cells and macrophages inhibits nerve regeneration in aged rats. Neurobiol Aging. 2016;45:1–9.
Mosher KI, Andres RH, Fukuhara T, Bieri G, Hasegawa-Moriyama M, He Y, et al. Neural progenitor cells regulate microglia functions and activity. Nat Neurosci. 2012;15:1485–7.
Wu H-H, Bellmunt E, Scheib JL, Venegas V, Burkert C, Reichardt LF, et al. Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat Neurosci. 2009;12:1534–41.
Bradbury EJ, Burnside ER. Moving beyond the glial scar for spinal cord repair. Nat Commun. 2019;10:3879.
Trivedi A, Olivas AD, Noble-Haeusslein LJ. Inflammation and spinal cord injury: infiltrating leukocytes as determinants of injury and repair processes. Clin Neurosci Res. 2006;6:283–92.
Kopp MA, Liebscher T, Watzlawick R, Martus P, Laufer S, Blex C, et al. SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol. BMJ Open. 2016;6:e010651.
Xu J, Fan G, Chen S, Wu Y, Xu XM, Hsu CY. Methylprednisolone inhibition of TNF-alpha expression and NF-kB activation after spinal cord injury in rats. Brain Res Mol Brain Res. 1998;59:135–42.
Mothe AJ, Tassew NG, Shabanzadeh AP, Penheiro R, Vigouroux RJ, Huang L, et al. RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Sci Rep. 2017;7:10529.
Qian T, Guo X, Levi AD, Vanni S, Shebert RT, Sipski ML. High-dose methylprednisolone may cause myopathy in acute spinal cord injury patients. Spinal Cord. 2005;43:199–203.
Suberviola B, González-Castro A, Llorca J, Ortiz-Melón F, Miñambres E. Early complications of high-dose methylprednisolone in acute spinal cord injury patients. Injury. 2008;39:748–52.
Cerqueira SR, Oliveira JM, Silva NA, Leite-Almeida H, Ribeiro-Samy S, Almeida A, et al. Microglia response and in vivo therapeutic potential of methylprednisolone-loaded dendrimer nanoparticles in spinal cord injury. Small. 2013;9:738–49.
Kim YT, Caldwell JM, Bellamkonda RV. Nanoparticle-mediated local delivery of methylprednisolone after spinal cord injury. Biomaterials. 2009;30:2582–90.
Qi L, Jiang H, Cui X, Liang G, Gao M, Huang Z, et al. Synthesis of methylprednisolone loaded ibuprofen modified dextran based nanoparticles and their application for drug delivery in acute spinal cord injury. Oncotarget. 2017;8(59):99666–80.
Andrea Bighinati MLF, Gualandi C, Pannella M, Giuliani A, Beggiato S, Ferraro L, et al. Improved functional recovery in rat spinal cord injury induced by a drug combination administered with an implantable polymeric delivery system. J Neurotrauma. 2020;37:1708–19.
Saxena T, Loomis KH, Pai SB, Karumbaiah L, Gaupp E, Patil K, et al. Nanocarrier-mediated inhibition of macrophage migration inhibitory factor attenuates secondary injury after spinal cord injury. ACS Nano. 2015;9:1492–505.
Wu W, Lee S-Y, Wu X, Tyler JY, Wang H, Ouyang Z, et al. Neuroprotective ferulic acid (FA)–glycol chitosan (GC) nanoparticles for functional restoration of traumatically injured spinal cord. Biomaterials. 2014;35:2355–64.
Sun G, Yang S, Cai H, Shu Y, Han Q, Wang B, et al. Molybdenum disulfide nanoflowers mediated anti-inflammation macrophage modulation for spinal cord injury treatment. J Colloid Interface Sci. 2019;549:50–62.
Shi Y, Kim S, Huff TB, Borgens RB, Park K, Shi R, et al. Effective repair of traumatically injured spinal cord by nanoscale block copolymer micelles. Nat Nanotechnol. 2010;5:80–7.
Liu D, Chen J, Jiang T, Li W, Huang Y, Lu X, et al. Biodegradable spheres protect traumatically injured spinal cord by alleviating the glutamate-induced excitotoxicity. Adv Mater. 2018;30:1706032.
Gao W, Li J. Targeted siRNA delivery reduces nitric oxide mediated cell death after spinal cord injury. J Nanobiotechnol. 2017;15:38.
Liu Z, Jiang M, Kang T, Miao D, Gu G, Song Q, et al. Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration. Biomaterials. 2013;34:3870–81.
Ren H, Han M, Zhou J, Zheng Z-F, Lu P, Wang J-J, et al. Repair of spinal cord injury by inhibition of astrocyte growth and inflammatory factor synthesis through local delivery of flavopiridol in PLGA nanoparticles. Biomaterials. 2014;35:6585–94.
Wu J, Jiang H, Bi Q, Luo Q, Li J, Zhang Y, et al. Apamin-mediated actively targeted drug delivery for treatment of spinal cord injury: more than just a concept. Mol Pharm. 2014;11:3210–22.
This work was supported by startup funds by the University of Maryland School of Pharmacy, the New Investigator Award from the American Association of Colleges of Pharmacy (AACP), and the University of Maryland Baltimore Institute for Clinical and Translational Research (ICTR) Accelerated Translational Incubator Pilot Grant (NIH #1UL1TR003098) awarded to R.M.P.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Atanu Chakraborty and Andrew J. Ciciriello are co-first authors.
Guest Editors: Xiuling Lu and Aliasger K Salem
About this article
Cite this article
Chakraborty, A., Ciciriello, A.J., Dumont, C.M. et al. Nanoparticle-Based Delivery to Treat Spinal Cord Injury—a Mini-review. AAPS PharmSciTech 22, 101 (2021). https://doi.org/10.1208/s12249-021-01975-2
- spinal cord injury
- tissue engineering
- drug delivery