Skip to main content

Advertisement

SpringerLink
Log in

CNS Delivery of Nucleic Acid Therapeutics: Beyond the Blood–Brain Barrier and Towards Specific Cellular Targeting

  • Review Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Nucleic acid-based therapeutic molecules including small interfering RNA (siRNA), microRNA(miRNA), antisense oligonucleotides (ASOs), messenger RNA (mRNA), and DNA-based gene therapy have tremendous potential for treating diseases in the central nervous system (CNS). However, achieving clinically meaningful delivery to the brain and particularly to target cells and sub-cellular compartments is typically very challenging. Mediating cell-specific delivery in the CNS would be a crucial advance that mitigates off-target effects and toxicities. In this review, we describe these challenges and provide contemporary evidence of advances in cellular and sub-cellular delivery using a variety of delivery mechanisms and alternative routes of administration, including the nose-to-brain approach. Strategies to achieve subcellular localization, endosomal escape, cytosolic bioavailability, and nuclear transfer are also discussed. Ultimately, there are still many challenges to translating these experimental strategies into effective and clinically viable approaches for treating patients.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AAV:

Adeno-associated virus

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ASOs:

Antisense oligonucleotides

bp:

Base pairs

BBB:

Blood-brain barrier

BCSFB:

Blood cerebrospinal-fluid barrier

BDNF:

Brain-derived neurotrophic factor

CPP:

Cell-penetrating peptides

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CRISPR:

Clustered regularly interspaced short palindromic repeats

CED:

Convection-enhanced delivery

Cas9:

CRISPR-associated protein 9

GDNF:

Glial cell-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

HTT:

Huntingtin

HD:

Huntington’s disease

ICV:

Intracerebroventricular

IP:

Intraparenchymal

IT-CM:

Intrathecal—cisterna magna

IT-L:

Intrathecal – lumbar

IT:

Intrathecal

IV:

Intravenous

kDa:

Kilodalton

LNPs:

Lipid nanoparticles

MegNs:

Meganucleases

mRNA:

Messenger RNA

miRNA:

MicroRNA

MIND:

Minimally-Invasive Nasal Depot

MS:

Multiple sclerosis

MSA:

Multiple system atrophy

NPC:

Nuclear pore complex

ODN:

Oligonucleotide

PD:

Parkinson’s disease

PEI:

Polyethylenimine

RVG:

Rabies virus glycoprotein

shRNA:

Short hairpin RNA

siRNA:

Short interfering RNA

SMA:

Spinal muscular atrophy

SOD1:

Superoxide dismutase 1

TALENs:

Transcription activator-like effector nuclease

TfR:

Transferrin receptor

ZFNs:

Zinc finger nucleases

References

  1. Simonato M, Bennett J, Boulis NM, Castro MG, Fink DJ, Goins WF, et al. Progress in gene therapy for neurological disorders. Nat Rev Neurol. 2013;9(5):277–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lima Giacobbo B, Doorduin J, Klein HC, Dierckx R, Bromberg E, de Vries EFJ. Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation. Mol Neurobiol. 2019;56(5):3295–312.

    Article  CAS  PubMed  Google Scholar 

  3. Nagabhushan Kalburgi S, Khan NN, Gray SJ. Recent gene therapy advancements for neurological diseases. Discov Med. 2013;15(81):111–9.

    PubMed  Google Scholar 

  4. Piguet F, Alves S, Cartier N. Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future. Hum Gene Ther. 2017;28(11):988–1003.

    Article  CAS  PubMed  Google Scholar 

  5. Cicalese MP, Aiuti A. New perspectives in gene therapy for inherited disorders. Pediatr Allergy Immunol. 2020;31(Suppl 24):5–7.

    Article  PubMed  Google Scholar 

  6. Sung YK, Kim SW. Recent advances in the development of gene delivery systems. Biomater Res. 2019;23(1):8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bulaklak K, Gersbach CA. The once and future gene therapy. Nat Commun. 2020;11(1):5820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Papanikolaou E, Bosio A. The Promise and the Hope of Gene Therapy. Front Genome Ed. 2021;3:618346.

  9. Pan X, Veroniaina H, Su N, Sha K, Jiang F, Wu Z, et al. Applications and developments of gene therapy drug delivery systems for genetic diseases. Asian J Pharm Sci. 2021;16(6):687–703.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Alagoz M, Kherad N. Advance genome editing technologies in the treatment of human diseases: CRISPR therapy (Review). Int J Mol Med. 2020;46(2):521–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yamada Y. Nucleic Acid Drugs-Current Status, Issues, and Expectations for Exosomes. Cancers. 2021;13(19):5002.

  12. Mendes BB, Conniot J, Avital A, Yao D, Jiang X, Zhou X, et al. Nanodelivery of nucleic acids. Nature Rev Methods Primers. 2022;2:24.

  13. Khalil AM. The genome editing revolution: review. J Genet Eng Biotechnol. 2020;18(1):68.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pezzoli D, Chiesa R, De Nardo L, Candiani G. We still have a long way to go to effectively deliver genes! J Appl Biomater Funct Mater. 2012;10(2):82–91.

    CAS  PubMed  Google Scholar 

  15. Klug B, Celis P, Carr M, Reinhardt J. Regulatory structures for gene therapy medicinal products in the European Union. Methods Enzymol. 2012;507:337–54.

    Article  CAS  PubMed  Google Scholar 

  16. Paunovska K, Loughrey D, Dahlman JE. Drug delivery systems for RNA therapeutics. Nat Rev Genet. 2022;23(5):265–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Deverman BE, Ravina BM, Bankiewicz KS, Paul SM, Sah DWY. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discovery. 2018;17(9):641–59.

    Article  CAS  PubMed  Google Scholar 

  18. Bobbin ML, Rossi JJ. RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise? Annu Rev Pharmacol Toxicol. 2016;56:103–22.

    Article  CAS  PubMed  Google Scholar 

  19. Lorenzer C, Dirin M, Winkler AM, Baumann V, Winkler J. Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics. J Control Release. 2015;203:1–15.

    Article  CAS  PubMed  Google Scholar 

  20. Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 2016;44(14):6549–63.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sridharan K, Gogtay NJ. Therapeutic nucleic acids: current clinical status. Br J Clin Pharmacol. 2016;82(3):659–72.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev. 2015;87:46–51.

    Article  CAS  PubMed  Google Scholar 

  23. DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener A, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9(374):eaag0481.

  24. Höck J, Meister G. The Argonaute protein family. Genome Biol. 2008;9(2):210.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu Y, Guo Y, An S, Kuang Y, He X, Ma H, et al. Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain-targeted nanoparticles in a rat model of Parkinson’s disease. PLoS One. 2013;8(5):e62905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu KW, Chen ZY, Hou TS. Protective effect of liposome-mediated glial cell line-derived neurotrophic factor gene transfer in vivo on motoneurons following spinal cord injury in rats. Chin J Traumatol = Zhonghua chuang shang za zhi. 2004;7(5):275–9.

  27. Alarcón-Arís D, Pavia-Collado R, Miquel L, Cóppola V, Ferrés-Coy A, Ruiz-Bronchal E, et al. Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson’s disease-like mouse model and in monkeys. EBioMedicine. 2020;59:102944.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wong E, Liao GP, Chang JC, Xu P, Li YM, Greengard P. GSAP modulates γ-secretase specificity by inducing conformational change in PS1. Proc Natl Acad Sci USA. 2019;116(13):6385–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yoon HH, Ye S, Lim S, Jo A, Lee H, Hong F, et al. CRISPR-Cas9 Gene Editing Protects from the A53T-SNCA Overexpression-Induced Pathology of Parkinson’s Disease In Vivo. The CRISPR journal. 2022;5(1):95–108.

    Article  CAS  PubMed  Google Scholar 

  30. Niu S, Zhang L-K, Zhang L, Zhuang S, Zhan X, Chen W-Y, et al. Inhibition by Multifunctional Magnetic Nanoparticles Loaded with Alpha-Synuclein RNAi Plasmid in a Parkinson’s Disease Model. Theranostics. 2017;7(2):344–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gao Y, Wang Z-Y, Zhang J, Zhang Y, Huo H, Wang T, et al. RVG-Peptide-Linked Trimethylated Chitosan for Delivery of siRNA to the Brain. Biomacromol. 2014;15(3):1010–8.

    Article  CAS  Google Scholar 

  32. Galloway DA, Blandford SN, Berry T, Williams JB, Stefanelli M, Ploughman M, et al. miR-223 promotes regenerative myeloid cell phenotype and function in the demyelinated central nervous system. Glia. 2019;67(5):857–69.

    Article  PubMed  Google Scholar 

  33. Jimenez-Mateos EM, Engel T, Merino-Serrais P, Fernaud-Espinosa I, Rodriguez-Alvarez N, Reynolds J, et al. Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus. Brain Struct Funct. 2015;220(4):2387–99.

    Article  CAS  PubMed  Google Scholar 

  34. Lin C-Y, Perche F, Ikegami M, Uchida S, Kataoka K, Itaka K. Messenger RNA-based therapeutics for brain diseases: An animal study for augmenting clearance of beta-amyloid by intracerebral administration of neprilysin mRNA loaded in polyplex nanomicelles. J Control Release. 2016;235:268–75.

    Article  CAS  PubMed  Google Scholar 

  35. Edinger D, Wagner E. Bioresponsive polymers for the delivery of therapeutic nucleic acids. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2011;3(1):33–46.

    Article  CAS  PubMed  Google Scholar 

  36. Vaseghi G, Rafiee L, Javanmard SH. Non-viral Delivery Systems for Breast Cancer Gene Therapy. Curr Gene Ther. 2017;17(2):147–53.

    Article  CAS  PubMed  Google Scholar 

  37. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15(8):541–55.

    Article  CAS  PubMed  Google Scholar 

  38. Crawford L, Rosch J, Putnam D. Concepts, technologies, and practices for drug delivery past the blood-brain barrier to the central nervous system. J Control Release. 2016;240:251–66.

    Article  CAS  PubMed  Google Scholar 

  39. Fumoto S, Yamamoto T, Okami K, Maemura Y, Terada C, Yamayoshi A, et al. Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs. Pharmaceutics. 2021;13(2):159.

  40. Luissint AC, Artus C, Glacial F, Ganeshamoorthy K, Couraud PO. Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS. 2012;9(1):23.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Dias N, Stein CA. Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther. 2002;1(5):347–55.

    CAS  PubMed  Google Scholar 

  42. Layzer JM, McCaffrey AP, Tanner AK, Huang Z, Kay MA, Sullenger BA. In vivo activity of nuclease-resistant siRNAs. RNA (New York, NY). 2004;10(5):766–71.

    Article  CAS  Google Scholar 

  43. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017;35(3):238–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wan WB, Seth PP. The Medicinal Chemistry of Therapeutic Oligonucleotides. J Med Chem. 2016;59(21):9645–67.

  45. Boo SH, Kim YK. The emerging role of RNA modifications in the regulation of mRNA stability. Exp Mol Med. 2020;52(3):400–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Corey DR. Chemical modification: the key to clinical application of RNA interference? J Clin Investig. 2007;117(12):3615–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lukacs GL, Haggie P, Seksek O, Lechardeur D, Freedman N, Verkman AS. Size-dependent DNA mobility in cytoplasm and nucleus. J Biol Chem. 2000;275(3):1625–9.

    Article  CAS  PubMed  Google Scholar 

  48. Suh J, Dawson M, Hanes J. Real-time multiple-particle tracking: applications to drug and gene delivery. Adv Drug Deliv Rev. 2005;57(1):63–78.

    Article  CAS  PubMed  Google Scholar 

  49. Vázquez E, Ferrer-Miralles N, Villaverde A. Peptide-assisted traffic engineering for nonviral gene therapy. Drug Discovery Today. 2008;13(23):1067–74.

    Article  PubMed  Google Scholar 

  50. Wong SY, Pelet JM, Putnam D. Polymer systems for gene delivery—Past, present, and future. Prog Polym Sci. 2007;32(8):799–837.

    Article  CAS  Google Scholar 

  51. Prasuhn J, Brüggemann N. Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson's Disease. Genes. 2021;12(11):1840.

  52. Morris JA, Boshoff CH, Schor NF, Wong LM, Gao G, Davidson BL. Next-generation strategies for gene-targeted therapies of central nervous system disorders: A workshop summary. Mol Ther. 2021;29(12):3332–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hsu P-H, Wei K-C, Huang C-Y, Wen C-J, Yen T-C, Liu C-L, et al. Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound. PLoS ONE. 2013;8(2):e57682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang PP, Frazier J, Brem H. Local drug delivery to the brain. Adv Drug Deliv Rev. 2002;54(7):987–1013.

    Article  CAS  PubMed  Google Scholar 

  55. Sadekar SS, Bowen M, Cai H, Jamalian S, Rafidi H, Shatz-Binder W, et al. Translational Approaches for Brain Delivery of Biologics via Cerebrospinal Fluid. Clin Pharmacol Ther. 2022;111(4):826–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Perez BA, Shutterly A, Chan YK, Byrne BJ, Corti M. Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases. Brain Sci. 2020;10(2):119.

  57. Scarpa M, Bellettato CM, Lampe C, Begley DJ. Neuronopathic lysosomal storage disorders: Approaches to treat the central nervous system. Best Pract Res Clin Endocrinol Metab. 2015;29(2):159–71.

    Article  CAS  PubMed  Google Scholar 

  58. Alam MI, Beg S, Samad A, Baboota S, Kohli K, Ali J, et al. Strategy for effective brain drug delivery. Eur J Pharm Sci. 2010;40(5):385–403.

    Article  CAS  PubMed  Google Scholar 

  59. Yadav DB, Maloney JA, Wildsmith KR, Fuji RN, Meilandt WJ, Solanoy H, et al. Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates. Br J Pharmacol. 2017;174(22):4173–85.

  60. Tan J-KY, Sellers DL, Pham B, Pun SH, Horner PJ. Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System. Front Mol Neurosci. 2016;9:108.

  61. Pardridge WM. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 2011;8(1):7.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Sci Transl Med. 2012;4(147):147ra111.

  63. Harbaugh RE, Saunders RL, Reeder RF. Use of implantable pumps for central nervous system drug infusions to treat neurological disease. Neurosurgery. 1988;23(6):693–8.

    Article  CAS  PubMed  Google Scholar 

  64. Scheld WM. Drug delivery to the central nervous system: general principles and relevance to therapy for infections of the central nervous system. Rev Infect Dis. 1989;11(Suppl 7):S1669–90.

    Article  CAS  PubMed  Google Scholar 

  65. Bellettato CM, Scarpa M. Possible strategies to cross the blood–brain barrier. Ital J Pediatr. 2018;44(2):131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Taghian T, Marosfoi MG, Puri AS, Cataltepe OI, King RM, Diffie EB, et al. A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna. Mol Ther. 2020;28(2):411–21.

    Article  CAS  PubMed  Google Scholar 

  67. Hinderer C, Bell P, Katz N, Vite CH, Louboutin JP, Bote E, et al. Evaluation of Intrathecal Routes of Administration for Adeno-Associated Viral Vectors in Large Animals. Hum Gene Ther. 2018;29(1):15–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hinderer C, Bell P, Vite CH, Louboutin JP, Grant R, Bote E, et al. Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna. Mol Ther Methods Clin Dev. 2014;1:14051.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wurster CD, Winter B, Wollinsky K, Ludolph AC, Uzelac Z, Witzel S, et al. Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients. J Neurol. 2019;266(1):183–94.

    Article  PubMed  Google Scholar 

  70. Calias P, Banks WA, Begley D, Scarpa M, Dickson P. Intrathecal delivery of protein therapeutics to the brain: A critical reassessment. Pharmacol Ther. 2014;144(2):114–22.

    Article  CAS  PubMed  Google Scholar 

  71. Samaranch L, Bringas J, Pivirotto P, Sebastian WS, Forsayeth J, Bankiewicz K. Cerebellomedullary Cistern Delivery for AAV-Based Gene Therapy: A Technical Note for Nonhuman Primates. Human Gene Ther Methods. 2016;27(1):13–6.

    Article  CAS  Google Scholar 

  72. Polikov VS, Tresco PA, Reichert WM. Response of brain tissue to chronically implanted neural electrodes. J Neurosci Methods. 2005;148(1):1–18.

    Article  PubMed  Google Scholar 

  73. Potts MB, Silvestrini MT, Lim DA. Devices for cell transplantation into the central nervous system: Design considerations and emerging technologies. Surg Neurol Int. 2013;4(Suppl 1):S22-30.

    PubMed  PubMed Central  Google Scholar 

  74. Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5(2):79–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mehta AM, Sonabend AM, Bruce JN. Convection-Enhanced Delivery. Neurotherapeutics. 2017;14(2):358–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen MY, Lonser RR, Morrison PF, Governale LS, Oldfield EH. Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue—cannula sealing time. J Neurosurg. 1999;90(2):315–20.

  77. Monani UR. Spinal Muscular Atrophy: A Deficiency in a Ubiquitous Protein; a Motor Neuron-Specific Disease. Neuron. 2005;48(6):885–95.

    Article  CAS  PubMed  Google Scholar 

  78. Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet (London, England). 2007;369(9578):2031–41.

    Article  CAS  PubMed  Google Scholar 

  79. Ström AL, Gal J, Shi P, Kasarskis EJ, Hayward LJ, Zhu H. Retrograde axonal transport and motor neuron disease. J Neurochem. 2008;106(2):495–505.

    Article  PubMed  PubMed Central  Google Scholar 

  80. D’Souza AA, Kutlehria S, Huang D, Bleier BS, Amiji MM. Nasal delivery of nanotherapeutics for CNS diseases: challenges and opportunities. Nanomedicine. 2021;16(30):2651–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Padmakumar S, Jones G, Khorkova O, Hsiao J, Kim J, Bleier BS, et al. Osmotic core-shell polymeric implant for sustained BDNF AntagoNAT delivery in CNS using minimally invasive nasal depot (MIND) approach. Biomaterials. 2021;276:120989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Padmakumar S, Jones G, Pawar G, Khorkova O, Hsiao J, Kim J, et al. Minimally Invasive Nasal Depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain. J Control Release. 2021;331:176–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Holm A, Hansen SN, Klitgaard H, Kauppinen S. Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases. RNA Biol. 2022;19(1):594–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Haché M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, et al. Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. J Child Neurol. 2016;31(7):899–906.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bortolani S, Stura G, Ventilii G, Vercelli L, Rolle E, Ricci F, et al. Intrathecal administration of nusinersen in adult and adolescent patients with spinal muscular atrophy and scoliosis: Transforaminal versus conventional approach. Neuromuscul Dis NMD. 2019;29(10):742–6.

    Article  Google Scholar 

  86. Cordts I, Lingor P, Friedrich B, Pernpeintner V, Zimmer C, Deschauer M, et al. Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy. Ther Adv Neurol Disord. 2020;13:1756286419887616.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Jimenez-Mateos EM, Engel T, Merino-Serrais P, McKiernan RC, Tanaka K, Mouri G, et al. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med. 2012;18(7):1087–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhu D, Schieferecke AJ, Lopez PA, Schaffer DV. Adeno-Associated Virus Vector for Central Nervous System Gene Therapy. Trends Mol Med. 2021;27(6):524–37.

    Article  CAS  PubMed  Google Scholar 

  89. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discovery. 2020;19(10):673–94.

    Article  CAS  PubMed  Google Scholar 

  90. Helmschrodt C, Höbel S, Schöniger S, Bauer A, Bonicelli J, Gringmuth M, et al. Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce α-Synuclein Expression in a Model of Parkinson’s Disease. Mol Ther Nucleic Acids. 2017;9:57–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hirunagi T, Sahashi K, Tachikawa K, Leu AI, Nguyen M, Mukthavaram R, et al. Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS. Mol Ther Nucleic Acids. 2021;24:1–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nabhan JF, Wood KM, Rao VP, Morin J, Bhamidipaty S, LaBranche TP, et al. Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia. Sci Rep. 2016;6(1):20019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Godinho B, Gilbert JW, Haraszti RA, Coles AH, Biscans A, Roux L, et al. Pharmacokinetic Profiling of Conjugated Therapeutic Oligonucleotides: A High-Throughput Method Based Upon Serial Blood Microsampling Coupled to Peptide Nucleic Acid Hybridization Assay. Nucleic Acid Ther. 2017;27(6):323–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Nikan M, Osborn MF, Coles AH, Godinho BM, Hall LM, Haraszti RA, et al. Docosahexaenoic Acid Conjugation Enhances Distribution and Safety of siRNA upon Local Administration in Mouse Brain. Mol Ther Nucleic Acids. 2016;5(8):e344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nikan M, Osborn MF, Coles AH, Biscans A, Godinho BMDC, Haraszti RA, et al. Synthesis and Evaluation of Parenchymal Retention and Efficacy of a Metabolically Stable O-Phosphocholine-N-docosahexaenoyl-l-serine siRNA Conjugate in Mouse Brain. Bioconjug Chem. 2017;28(6):1758–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Brown KM, Nair JK, Janas MM, Anglero-Rodriguez YI, Dang LTH, Peng H, et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat Biotechnol. 2022;40(10):1500–1508.

  97. Das S, Mishra KP, Ganju L, Singh SB. Intranasally delivered small interfering RNA-mediated suppression of scavenger receptor Mac-1 attenuates microglial phenotype switching and working memory impairment following hypoxia. Neuropharmacology. 2018;137:240–55.

    Article  CAS  PubMed  Google Scholar 

  98. Rodriguez M, Lapierre J, Ojha CR, Kaushik A, Batrakova E, Kashanchi F, et al. Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation. Sci Rep. 2017;7(1):1862.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Dhaliwal HK, Fan Y, Kim J, Amiji MM. Intranasal Delivery and Transfection of mRNA Therapeutics in the Brain Using Cationic Liposomes. Mol Pharm. 2020;17(6):1996–2005.

    Article  CAS  PubMed  Google Scholar 

  100. Sanchez-Ramos J, Song S, Kong X, Foroutan P, Martinez G, Dominguez-Viqueria W, et al. Chitosan-Mangafodipir nanoparticles designed for intranasal delivery of siRNA and DNA to brain. J Drug Deliv Sci Technol. 2018;43:453–60.

    Article  CAS  PubMed  Google Scholar 

  101. Kanazawa T, Akiyama F, Kakizaki S, Takashima Y, Seta Y. Delivery of siRNA to the brain using a combination of nose-to-brain delivery and cell-penetrating peptide-modified nano-micelles. Biomaterials. 2013;34(36):9220–6.

    Article  CAS  PubMed  Google Scholar 

  102. Simão Carlos MI, Zheng K, Garrett N, Arifin N, Workman DG, Kubajewska I, et al. Limiting the level of tertiary amines on polyamines leads to biocompatible nucleic acid vectors. Int J Pharm. 2017;526(1):106–24.

    Article  PubMed  Google Scholar 

  103. Li Y, Wang J, Lee CG, Wang CY, Gao SJ, Tang GP, et al. CNS gene transfer mediated by a novel controlled release system based on DNA complexes of degradable polycation PPE-EA: a comparison with polyethylenimine/DNA complexes. Gene Ther. 2004;11(1):109–14.

    Article  CAS  PubMed  Google Scholar 

  104. Alvarez-Maya I, Navarro-Quiroga I, Meraz-Ríos MA, Aceves J, Martinez-Fong D. In vivo gene transfer to dopamine neurons of rat substantia nigra via the high-affinity neurotensin receptor. Mol Med. 2001;7(3):186–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Alarcón-Arís D, Recasens A, Galofré M, Carballo-Carbajal I, Zacchi N, Ruiz-Bronchal E, et al. Selective α-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson’s Disease. Mol Ther. 2018;26(2):550–67.

    Article  PubMed  Google Scholar 

  106. Su Y, Sun B, Gao X, Dong X, Fu L, Zhang Y, et al. Intranasal Delivery of Targeted Nanoparticles Loaded With miR-132 to Brain for the Treatment of Neurodegenerative Diseases. Front Pharmacol. 2020;11:1165.

  107. Wen MM. Olfactory targeting through intranasal delivery of biopharmaceutical drugs to the brain: current development. Discov Med. 2011;11(61):497–503.

    PubMed  Google Scholar 

  108. Islam SU, Shehzad A, Ahmed MB, Lee YS. Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders. Molecules (Basel, Switzerland). 2020;25(8):1929.

  109. Lee D, Minko T. Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier. Pharmaceutics. 2021;13(12):2049.

  110. Yadav S, Gandham SK, Panicucci R, Amiji MM. Intranasal brain delivery of cationic nanoemulsion-encapsulated TNFα siRNA in prevention of experimental neuroinflammation. Nanomedicine. 2016;12(4):987–1002.

    Article  CAS  PubMed  Google Scholar 

  111. Samaridou E, Walgrave H, Salta E, Álvarez DM, Castro-López V, Loza M, et al. Nose-to-brain delivery of enveloped RNA - cell permeating peptide nanocomplexes for the treatment of neurodegenerative diseases. Biomaterials. 2020;230:119657.

    Article  CAS  PubMed  Google Scholar 

  112. Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gromnicova R, Davies HA, Sreekanthreddy P, Romero IA, Lund T, Roitt IM, et al. Glucose-Coated Gold Nanoparticles Transfer across Human Brain Endothelium and Enter Astrocytes In Vitro. PLoS One. 2013;8(12):e81043.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Pardridge WM. Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain. Front Aging Neurosci. 2019;11:373.

    Article  CAS  PubMed  Google Scholar 

  115. Pardridge WM. Blood-brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses. J Control Release. 2007;122(3):345–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kimura S, Harashima H. Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB. Pharmaceutics. 2020;12(12):1216.

  117. Banks WA, Greig NH. Small molecules as central nervous system therapeutics: old challenges, new directions, and a philosophic divide. Future Med Chem. 2019;11(6):489–93.

    Article  CAS  PubMed  Google Scholar 

  118. Ko YT, Bhattacharya R, Bickel U. Liposome encapsulated polyethylenimine/ODN polyplexes for brain targeting. J Control Release. 2009;133(3):230–7.

    Article  CAS  PubMed  Google Scholar 

  119. da Cruz MT, Cardoso AL, de Almeida LP, Simões S, de Lima MC. Tf-lipoplex-mediated NGF gene transfer to the CNS: neuronal protection and recovery in an excitotoxic model of brain injury. Gene Ther. 2005;12(16):1242–52.

    Article  PubMed  Google Scholar 

  120. Xia C-F, Zhang Y, Zhang Y, Boado RJ, Pardridge WM. Intravenous siRNA of Brain Cancer with Receptor Targeting and Avidin-Biotin Technology. Pharm Res. 2007;24(12):2309–16.

    Article  CAS  PubMed  Google Scholar 

  121. Min HS, Kim HJ, Naito M, Ogura S, Toh K, Hayashi K, et al. Systemic Brain Delivery of Antisense Oligonucleotides across the Blood-Brain Barrier with a Glucose-Coated Polymeric Nanocarrier. Angew Chem Int Ed. 2020;59(21):8173–80.

    Article  CAS  Google Scholar 

  122. An S, Kuang Y, Shen T, Li J, Ma H, Guo Y, et al. Brain-targeting delivery for RNAi neuroprotection against cerebral ischemia reperfusion injury. Biomaterials. 2013;34(35):8949–59.

    Article  CAS  PubMed  Google Scholar 

  123. Yuan Z, Zhao L, Zhang Y, Li S, Pan B, Hua L, et al. Inhibition of glioma growth by a GOLPH3 siRNA-loaded cationic liposomes. J Neurooncol. 2018;140(2):249–60.

    Article  CAS  PubMed  Google Scholar 

  124. Heidel JD, Yu Z, Liu JY, Rele SM, Liang Y, Zeidan RK, et al. Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proc Natl Acad Sci USA. 2007;104(14):5715–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–5.

    Article  CAS  PubMed  Google Scholar 

  126. Zhang R, Fu Y, Cheng M, Ma W, Zheng N, Wang Y, et al. sEVs(RVG) selectively delivers antiviral siRNA to fetus brain, inhibits ZIKV infection and mitigates ZIKV-induced microcephaly in mouse model. Mol Ther. 2022;30(5):2078–91.

    Article  CAS  PubMed  Google Scholar 

  127. Ren X, Zhao Y, Xue F, Zheng Y, Huang H, Wang W, et al. Exosomal DNA Aptamer Targeting α-Synuclein Aggregates Reduced Neuropathological Deficits in a Mouse Parkinson’s Disease Model. Molecular Therapy Nucleic Acids. 2019;17:726–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Cooper JM, Wiklander PB, Nordin JZ, Al-Shawi R, Wood MJ, Vithlani M, et al. Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov Disord. 2014;29(12):1476–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Banks WA, Sharma P, Bullock KM, Hansen KM, Ludwig N, Whiteside TL. Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. International J Mol Sci. 2020;21(12):4407.

  130. Chivet M, Javalet C, Laulagnier K, Blot B, Hemming FJ, Sadoul R. Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons. J Extracell Vesicles. 2014;3:24722-.

  131. Fletcher AM, Kowalczyk TH, Padegimas L, Cooper MJ, Yurek DM. Transgene expression in the striatum following intracerebral injections of DNA nanoparticles encoding for human glial cell line-derived neurotrophic factor. Neuroscience. 2011;194:220–6.

    Article  CAS  PubMed  Google Scholar 

  132. Barbato G, Nisticò R, Triaca V. Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy. Front Pharmacol. 2022;13:786475.

  133. Lin J, Jo SB, Kim TH, Kim HW, Chew SY. RNA interference in glial cells for nerve injury treatment. J Tissue Eng. 2020;11:2041731420939224.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Song KH, Harvey BK, Borden MA. State-of-the-art of microbubble-assisted blood-brain barrier disruption. Theranostics. 2018;8(16):4393–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Meng Y, Hynynen K, Lipsman N. Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat Rev Neurol. 2021;17(1):7–22.

    Article  PubMed  Google Scholar 

  136. Burgess A, Huang Y, Querbes W, Sah DW, Hynynen K. Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. J Control Release. 2012;163(2):125–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhao Z, Ukidve A, Kim J, Mitragotri S. Targeting Strategies for Tissue-Specific Drug Delivery. Cell. 2020;181(1):151–67.

    Article  CAS  PubMed  Google Scholar 

  138. Tschuch C, Schulz A, Pscherer A, Werft W, Benner A, Hotz-Wagenblatt A, et al. Off-target effects of siRNA specific for GFP. BMC Mol Biol. 2008;9:60.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Persengiev SP, Zhu X, Green MR. Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs). RNA (New York, NY). 2004;10(1):12–8.

    Article  CAS  Google Scholar 

  140. Jackson AL, Linsley PS. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discovery. 2010;9(1):57–67.

    Article  CAS  PubMed  Google Scholar 

  141. Valori CF, Possenti A, Brambilla L, Rossi D. Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders. Cells. 2021;10(8):2019.

  142. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430(7000):631–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Tosi G, Pederzoli F, Belletti D, Vandelli MA, Forni F, Duskey JT, et al. Nanomedicine in Alzheimer’s disease: Amyloid beta targeting strategy. Prog Brain Res. 2019;245:57–88.

    Article  PubMed  Google Scholar 

  144. Gouras GK, Almeida CG, Takahashi RH. Intraneuronal Aβ accumulation and origin of plaques in Alzheimer’s disease. Neurobiol Aging. 2005;26(9):1235–44.

    Article  CAS  PubMed  Google Scholar 

  145. Ramachandran PS, Keiser MS, Davidson BL. Recent advances in RNA interference therapeutics for CNS diseases. Neurotherapeutics. 2013;10(3):473–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA. Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biochim Biophys Acta (BBA) Biomembr. 2011;1808(5):1380–99.

  147. Li T, Quan Lan J, Fredholm BB, Simon RP, Boison D. Adenosine dysfunction in astrogliosis: cause for seizure generation? Neuron Glia Biol. 2007;3(4):353–66.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Cepeda C, Wu N, André VM, Cummings DM, Levine MS. The corticostriatal pathway in Huntington’s disease. Prog Neurobiol. 2007;81(5–6):253–71.

    Article  CAS  PubMed  Google Scholar 

  149. Shin J-Y, Fang Z-H, Yu Z-X, Wang C-E, Li S-H, Li X-J. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol. 2005;171(6):1001–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Acevedo-Torres K, Berríos L, Rosario N, Dufault V, Skatchkov S, Eaton MJ, et al. Mitochondrial DNA damage is a hallmark of chemically induced and the R6/2 transgenic model of Huntington’s disease. DNA Repair. 2009;8(1):126–36.

    Article  CAS  PubMed  Google Scholar 

  151. Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the Trigeminal System in Migraine. Headache. 2019;59(5):659–81.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltrán E, et al. Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain. 2017;18(1):96.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Peeraully T. Multiple System Atrophy. Semin Neurol. 2014;34(02):174–81.

    Article  PubMed  Google Scholar 

  155. Ntetsika T, Papathoma P-E, Markaki I. Novel targeted therapies for Parkinson’s disease. Mol Med. 2021;27(1):17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Newland B, Dunnett SB, Dowd E. Targeting delivery in Parkinson’s disease. Drug Discovery Today. 2016;21(8):1313–20.

    Article  CAS  PubMed  Google Scholar 

  157. Boudreau RL, Rodríguez-Lebrón E, Davidson BL. RNAi medicine for the brain: progresses and challenges. Hum Mol Genet. 2011;20(R1):R21–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kraus-Perrotta C, Lagalwar S. Expansion, mosaicism and interruption: mechanisms of the CAG repeat mutation in spinocerebellar ataxia type 1. Cerebellum Ataxias. 2016;3(1):20.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Przedborski S, Vila M, Jackson-Lewis V. Neurodegeneration: what is it and where are we? J Clin Investig. 2003;111(1):3–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Budday S, Ovaert TC, Holzapfel GA, Steinmann P, Kuhl E. Fifty Shades of Brain: A Review on the Mechanical Testing and Modeling of Brain Tissue. Arch Comput Methods Eng. 2020;27(4):1187–230.

    Article  Google Scholar 

  161. Pfisterer U, Khodosevich K. Neuronal survival in the brain: neuron type-specific mechanisms. Cell Death & Disease. 2017;8(3):e2643-e.

  162. Dugger BN, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2017;9(7):a028035.

  163. Gorman AM. Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med. 2008;12(6a):2263–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Jin G-Z, Chakraborty A, Lee J-H, Knowles JC, Kim H-W. Targeting with nanoparticles for the therapeutic treatment of brain diseases. J Tissue Eng. 2020;11:2041731419897460.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Pennartz CMA, Dora S, Muckli L, Lorteije JAM. Towards a Unified View on Pathways and Functions of Neural Recurrent Processing. Trends Neurosci. 2019;42(9):589–603.

    Article  CAS  PubMed  Google Scholar 

  166. Slow EJ, Graham RK, Hayden MR. To be or not to be toxic: aggregations in Huntington and Alzheimer disease. Trends Genet TIG. 2006;22(8):408–11.

    Article  CAS  PubMed  Google Scholar 

  167. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, Quack G. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1–40). Brain Res. 2002;958(1):210–21.

    Article  CAS  PubMed  Google Scholar 

  168. Ikonomovic MD, Mizukami K, Warde D, Sheffield R, Hamilton R, Wenthold RJ, et al. Distribution of glutamate receptor subunit NMDAR1 in the hippocampus of normal elderly and patients with Alzheimer’s disease. Exp Neurol. 1999;160(1):194–204.

    Article  CAS  PubMed  Google Scholar 

  169. Cheyuo C, Aziz M, Wang P. Neurogenesis in Neurodegenerative Diseases: Role of MFG-E8. Front Neurosci. 2019;13:569.

  170. Herculano-Houzel S. The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci. 2009;3:31.

  171. Kwon EJ, Lasiene J, Jacobson BE, Park IK, Horner PJ, Pun SH. Targeted nonviral delivery vehicles to neural progenitor cells in the mouse subventricular zone. Biomaterials. 2010;31(8):2417–24.

    Article  CAS  PubMed  Google Scholar 

  172. Chu DS, Schellinger JG, Bocek MJ, Johnson RN, Pun SH. Optimization of Tet1 ligand density in HPMA-co-oligolysine copolymers for targeted neuronal gene delivery. Biomaterials. 2013;34(37):9632–7.

    Article  CAS  PubMed  Google Scholar 

  173. Garcia-Chica J, D Paraiso WK, Tanabe S, Serra D, Herrero L, Casals N, et al. An overview of nanomedicines for neuron targeting. Nanomedicine. 2020;15(16):1617–36.

  174. Lafon M. Rabies virus receptors. J Neurovirol. 2005;11(1):82–7.

    Article  CAS  PubMed  Google Scholar 

  175. Kumar P, Wu H, McBride JL, Jung K-E, Hee Kim M, Davidson BL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448(7149):39–43.

    Article  CAS  PubMed  Google Scholar 

  176. Wang P, Zheng X, Guo Q, Yang P, Pang X, Qian K, et al. Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of Alzheimer’s disease. J Control Release. 2018;279:220–33.

    Article  CAS  PubMed  Google Scholar 

  177. Zheng X, Pang X, Yang P, Wan X, Wei Y, Guo Q, et al. A hybrid siRNA delivery complex for enhanced brain penetration and precise amyloid plaque targeting in Alzheimer’s disease mice. Acta Biomater. 2017;49:388–401.

    Article  CAS  PubMed  Google Scholar 

  178. Kim SS, Ye C, Kumar P, Chiu I, Subramanya S, Wu H, et al. Targeted delivery of siRNA to macrophages for anti-inflammatory treatment. Mol Ther. 2010;18(5):993–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Tanaka H, Nakatani T, Furihata T, Tange K, Nakai Y, Yoshioka H, et al. In Vivo Introduction of mRNA Encapsulated in Lipid Nanoparticles to Brain Neuronal Cells and Astrocytes via Intracerebroventricular Administration. Mol Pharm. 2018;15(5):2060–7.

    Article  CAS  PubMed  Google Scholar 

  180. Zhang C, Gu Z, Shen L, Liu X, Lin H. In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System. Curr Pharm Biotechnol. 2019;20(1):56–62.

    Article  CAS  PubMed  Google Scholar 

  181. Kwon EJ, Skalak M, Lo BuR, Bhatia SN. Neuron-Targeted Nanoparticle for siRNA Delivery to Traumatic Brain Injuries. ACS Nano. 2016;10(8):7926–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Rungta RL, Choi HB, Lin PJ, Ko RW, Ashby D, Nair J, et al. Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain. Mol Ther Nucleic Acids. 2013;2(12):e136.

  183. Stevenson R, Samokhina E, Rossetti I, Morley JW, Buskila Y. Neuromodulation of Glial Function During Neurodegeneration. Front Cell Neurosci. 2020;14:278.

  184. Aamodt S. Focus on glia and disease. Nat Neurosci. 2007;10(11):1349.

  185. Kery R, Chen APF, Kirschen GW. Genetic targeting of astrocytes to combat neurodegenerative disease. Neural Regen Res. 2020;15(2):199–211.

    Article  CAS  PubMed  Google Scholar 

  186. Maragakis NJ, Rothstein JD. Glutamate Transporters in Neurologic Disease. Arch Neurol. 2001;58(3):365–70.

    Article  CAS  PubMed  Google Scholar 

  187. Neher JJ, Neniskyte U, Zhao J-W, Bal-Price A, Tolkovsky AM, Brown GC. Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death. J Immunol. 2011;186(8):4973.

    Article  CAS  PubMed  Google Scholar 

  188. Glezer I, Simard AR, Rivest S. Neuroprotective role of the innate immune system by microglia. Neuroscience. 2007;147(4):867–83.

    Article  CAS  PubMed  Google Scholar 

  189. Zhao N, Francis NL, Calvelli HR, Moghe PV. Microglia-targeting nanotherapeutics for neurodegenerative diseases. APL Bioengineering. 2020;4(3):030902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Gu X, Song Q, Zhang Q, Huang M, Zheng M, Chen J, et al. Clearance of two organic nanoparticles from the brain via the paravascular pathway. J Control Release. 2020;322:31–41.

    Article  CAS  PubMed  Google Scholar 

  191. Tang Y, Le W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol Neurobiol. 2016;53(2):1181–94.

    Article  CAS  PubMed  Google Scholar 

  192. Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11:98.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, et al. Activation of Toll-like Receptor 2 on Microglia Promotes Cell Uptake of Alzheimer Disease-associated Amyloid β Peptide*. J Biol Chem. 2006;281(6):3651–9.

    Article  CAS  PubMed  Google Scholar 

  194. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration. Cell. 2018;173(5):1073–81.

    Article  CAS  PubMed  Google Scholar 

  195. Wang J, Wang J, Wang J, Yang B, Weng Q, He Q. Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis. Front Pharmacol. 2019;10:286.

  196. Li K, Li J, Zheng J, Qin S. Reactive Astrocytes in Neurodegenerative Diseases. Aging Dis. 2019;10(3):664–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Phatnani H, Maniatis T. Astrocytes in neurodegenerative disease. Cold Spring Harb Perspect Biol. 2015;7(6):a020628.

  198. Izrael M, Slutsky SG, Revel M. Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease. Front Neurosci. 2020;14:824.

  199. Love S. Demyelinating diseases. J Clin Pathol. 2006;59(11):1151–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Georgiou E, Sidiropoulou K, Richter J, Papaneophytou C, Sargiannidou I, Kagiava A, et al. Gene therapy targeting oligodendrocytes provides therapeutic benefit in a leukodystrophy model. Brain. 2017;140(3):599–616.

    PubMed  PubMed Central  Google Scholar 

  201. Guo S, Cázarez-Márquez F, Jiao H, Foppen E, Korpel NL, Grootemaat AE, et al. Specific Silencing of Microglial Gene Expression in the Rat Brain by Nanoparticle-Based Small Interfering RNA Delivery. ACS Appl Mater Interfaces. 2022;14(4):5066–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Minami SS, Sun B, Popat K, Kauppinen T, Pleiss M, Zhou Y, et al. Selective targeting of microglia by quantum dots. J Neuroinflammation. 2012;9(1):22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Vu TQ, Maddipati R, Blute TA, Nehilla BJ, Nusblat L, Desai TA. Peptide-conjugated quantum dots activate neuronal receptors and initiate downstream signaling of neurite growth. Nano Lett. 2005;5(4):603–7.

    Article  CAS  PubMed  Google Scholar 

  204. Gao W, Li J. Targeted siRNA delivery reduces nitric oxide mediated cell death after spinal cord injury. J Nanobiotechnology. 2017;15(1):38.

    Article  PubMed  PubMed Central  Google Scholar 

  205. Maes ME, Colombo G, Schulz R, Siegert S. Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges. Neurosci Lett. 2019;707:134310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Delzor A, Escartin C, Déglon N. Lentiviral vectors: a powerful tool to target astrocytes in vivo. Curr Drug Targets. 2013;14(11):1336–46.

    Article  CAS  PubMed  Google Scholar 

  207. Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci. 2012;32(46):16129–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009;27(1):59–65.

    Article  CAS  PubMed  Google Scholar 

  209. Samaranch L, Salegio EA, San Sebastian W, Kells AP, Foust KD, Bringas JR, et al. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum Gene Ther. 2012;23(4):382–9.

    Article  CAS  PubMed  Google Scholar 

  210. Terashima T, Ogawa N, Nakae Y, Sato T, Katagi M, Okano J, et al. Gene Therapy for Neuropathic Pain through siRNA-IRF5 Gene Delivery with Homing Peptides to Microglia. Mol Ther Nucleic Acids. 2018;11:203–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Gu J, Al-Bayati K, Ho EA. Development of antibody-modified chitosan nanoparticles for the targeted delivery of siRNA across the blood-brain barrier as a strategy for inhibiting HIV replication in astrocytes. Drug Deliv Transl Res. 2017;7(4):497–506.

    Article  CAS  PubMed  Google Scholar 

  212. Akita H, Nakatani T, Kuroki K, Maenaka K, Tange K, Nakai Y, et al. Effect of hydrophobic scaffold on the cellular uptake and gene transfection activities of DNA-encapsulating liposomal nanoparticles via intracerebroventricular administration. Int J Pharm. 2015;490(1–2):142–5.

    Article  CAS  PubMed  Google Scholar 

  213. Rittchen S, Boyd A, Burns A, Park J, Fahmy TM, Metcalfe S, et al. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF). Biomaterials. 2015;56:78–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Querbes W, Ge P, Zhang W, Fan Y, Costigan J, Charisse K, et al. Direct CNS delivery of siRNA mediates robust silencing in oligodendrocytes. Oligonucleotides. 2009;19(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  215. Chen Q, Butler D, Querbes W, Pandey RK, Ge P, Maier MA, et al. Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery. J Control Release. 2010;144(2):227–32.

    Article  CAS  PubMed  Google Scholar 

  216. Gardlík R, Pálffy R, Hodosy J, Lukács J, Turna J, Celec P. Vectors and delivery systems in gene therapy. Med Sci Monit. 2005;11(4):Ra110–21.

  217. Sharma D, Arora S, Singh J, Layek B. A review of the tortuous path of nonviral gene delivery and recent progress. Int J Biol Macromol. 2021;183:2055–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Khalil IA, Kogure K, Akita H, Harashima H. Uptake pathways and subsequent intracellular trafficking in nonviral gene delivery. Pharmacol Rev. 2006;58(1):32–45.

    Article  CAS  PubMed  Google Scholar 

  219. Buck J, Grossen P, Cullis PR, Huwyler J, Witzigmann D. Lipid-Based DNA Therapeutics: Hallmarks of Non-Viral Gene Delivery. ACS Nano. 2019;13(4):3754–82.

    Article  CAS  PubMed  Google Scholar 

  220. Wagenaar TR, Tolstykh T, Shi C, Jiang L, Zhang J, Li Z, et al. Identification of the endosomal sorting complex required for transport-I (ESCRT-I) as an important modulator of anti-miR uptake by cancer cells. Nucleic Acids Res. 2015;43(2):1204–15.

    Article  CAS  PubMed  Google Scholar 

  221. Crooke ST, Wang S, Vickers TA, Shen W, Liang XH. Cellular uptake and trafficking of antisense oligonucleotides. Nat Biotechnol. 2017;35(3):230–7.

    Article  CAS  PubMed  Google Scholar 

  222. Schlich M, Palomba R, Costabile G, Mizrahy S, Pannuzzo M, Peer D, et al. Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles. Bioeng Transl Med. 2021;6(2):e10213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Taylor RE, Zahid M. Cell Penetrating Peptides, Novel Vectors for Gene Therapy. Pharmaceutics. 2020;12(3):225.

  224. Somiya M, Liu Q, Kuroda S. Current Progress of Virus-mimicking Nanocarriers for Drug Delivery. Nanotheranostics. 2017;1(4):415–29.

  225. Oehlke J, Scheller A, Wiesner B, Krause E, Beyermann M, Klauschenz E, et al. Cellular uptake of an alpha-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochem Biophys Acta. 1998;1414(1–2):127–39.

    Article  CAS  PubMed  Google Scholar 

  226. Li W, Nicol F, Szoka FC. GALA: a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. Adv Drug Deliv Rev. 2004;56(7):967–85.

    Article  CAS  PubMed  Google Scholar 

  227. Wyman TB, Nicol F, Zelphati O, Scaria PV, Plank C, Szoka FC Jr. Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochemistry. 1997;36(10):3008–17.

    Article  CAS  PubMed  Google Scholar 

  228. Melikov K, Chernomordik LV. Arginine-rich cell penetrating peptides: from endosomal uptake to nuclear delivery. Cell Mol Life Sci CMLS. 2005;62(23):2739–49.

    Article  CAS  PubMed  Google Scholar 

  229. Kichler A, Mason AJ, Bechinger B. Cationic amphipathic histidine-rich peptides for gene delivery. Biochem Biophys Acta. 2006;1758(3):301–7.

    Article  CAS  PubMed  Google Scholar 

  230. Sonawane ND, Szoka FC Jr, Verkman AS. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem. 2003;278(45):44826–31.

    Article  CAS  PubMed  Google Scholar 

  231. Medina-Kauwe LK, Xie J, Hamm-Alvarez S. Intracellular trafficking of nonviral vectors. Gene Ther. 2005;12(24):1734–51.

    Article  CAS  PubMed  Google Scholar 

  232. Xu Y, Szoka FC Jr. Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochemistry. 1996;35(18):5616–23.

    Article  CAS  PubMed  Google Scholar 

  233. Schaffer DV, Fidelman NA, Dan N, Lauffenburger DA. Vector unpacking as a potential barrier for receptor-mediated polyplex gene delivery. Biotechnol Bioeng. 2000;67(5):598–606.

    Article  CAS  PubMed  Google Scholar 

  234. Lorenz C, Fotin-Mleczek M, Roth G, Becker C, Dam TC, Verdurmen WP, et al. Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. RNA Biol. 2011;8(4):627–36.

    Article  CAS  PubMed  Google Scholar 

  235. Vermeulen LMP, Brans T, De Smedt SC, Remaut K, Braeckmans K. Methodologies to investigate intracellular barriers for nucleic acid delivery in non-viral gene therapy. Nano Today. 2018;21:74–90.

    Article  CAS  Google Scholar 

  236. Vaughan EE, DeGiulio JV, Dean DA. Intracellular trafficking of plasmids for gene therapy: mechanisms of cytoplasmic movement and nuclear import. Curr Gene Ther. 2006;6(6):671–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Mirzayans R, Aubin RA, Paterson MC. Differential expression and stability of foreign genes introduced into human fibroblasts by nuclear versus cytoplasmic microinjection. Mutat Res. 1992;281(2):115–22.

    Article  CAS  PubMed  Google Scholar 

  238. Sebestyén MG, Ludtke JJ, Bassik MC, Zhang G, Budker V, Lukhtanov EA, et al. DNA vector chemistry: The covalent attachment of signal peptides to plasmid DNA. Nat Biotechnol. 1998;16(1):80–5.

    Article  PubMed  Google Scholar 

  239. Mesika A, Grigoreva I, Zohar M, Reich Z. A regulated, NFkappaB-assisted import of plasmid DNA into mammalian cell nuclei. Mol Ther. 2001;3(5 Pt 1):653–7.

    Article  CAS  PubMed  Google Scholar 

  240. Vandenbroucke RE, Lucas B, Demeester J, De Smedt SC, Sanders NN. Nuclear accumulation of plasmid DNA can be enhanced by non-selective gating of the nuclear pore. Nucleic Acids Res. 2007;35(12):e86.

  241. Park KM, Kang HC, Cho JK, Chung IJ, Cho SH, Bae YH, et al. All-trans-retinoic acid (ATRA)-grafted polymeric gene carriers for nuclear translocation and cell growth control. Biomaterials. 2009;30(13):2642–52.

    Article  CAS  PubMed  Google Scholar 

  242. Charoensit P, Kawakami S, Higuchi Y, Yamashita F, Hashida M. Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice. Cancer Gene Ther. 2010;17(7):512–22.

    Article  CAS  PubMed  Google Scholar 

  243. Grandinetti G, Reineke TM. Exploring the Mechanism of Plasmid DNA Nuclear Internalization with Polymer-Based Vehicles. Mol Pharm. 2012;9(8):2256–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Grandinetti G, Smith AE, Reineke TM. Membrane and Nuclear Permeabilization by Polymeric pDNA Vehicles: Efficient Method for Gene Delivery or Mechanism of Cytotoxicity? Mol Pharm. 2012;9(3):523–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Durymanov MO, Yarutkin AV, Khramtsov YV, Rosenkranz AA, Sobolev AS. Live imaging of transgene expression in Cloudman S91 melanoma cells after polyplex-mediated gene delivery. J Control Release. 2015;215:73–81.

    Article  CAS  PubMed  Google Scholar 

  246. Kirchenbuechler I, Kirchenbuechler D, Elbaum M. Correlation between cationic lipid-based transfection and cell division. Exp Cell Res. 2016;345(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  247. Durymanov M, Reineke J. Non-viral Delivery of Nucleic Acids: Insight Into Mechanisms of Overcoming Intracellular Barriers. Front Pharmacol. 2018;9:971.

    Article  PubMed  PubMed Central  Google Scholar 

  248. Chowdhury EH. Nuclear targeting of viral and non-viral DNA. Expert Opin Drug Deliv. 2009;6(7):697–703.

    Article  CAS  PubMed  Google Scholar 

  249. Monzio Compagnoni G, Di Fonzo A, Corti S, Comi GP, Bresolin N, Masliah E. The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease. Mol Neurobiol. 2020;57(7):2959–80.

    Article  CAS  PubMed  Google Scholar 

  250. Reddy PH. Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer's disease. CNS Spectrums. 2009;14(8 Suppl 7):8–13; discussion 16–8.

  251. Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, Petersen RB, et al. Mitochondria: a therapeutic target in neurodegeneration. Biochem Biophys Acta. 2010;1802(1):212–20.

    CAS  PubMed  Google Scholar 

  252. Burchell VS, Gandhi S, Deas E, Wood NW, Abramov AY, Plun-Favreau H. Targeting mitochondrial dysfunction in neurodegenerative disease: Part I. Expert Opin Ther Targets. 2010;14(4):369–85.

    Article  CAS  PubMed  Google Scholar 

  253. Zhang Y, Yang H, Wei D, Zhang X, Wang J, Wu X, et al. Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases. Exploration. 2021;1(3):20210115.

    Article  Google Scholar 

  254. Tabish TA, Hamblin MR. Mitochondria-targeted nanoparticles (mitoNANO): An emerging therapeutic shortcut for cancer. Biomater Biosyst. 2021;3:100023.

    Article  Google Scholar 

  255. Lee J-M, Correia K, Loupe J, Kim K-H, Barker D, Hong EP, et al. CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset. Cell. 2019;178(4):887-900.e14.

    Article  Google Scholar 

  256. Kawaguchi Y, Wilson CJ, Augood SJ, Emson PC. Striatal interneurones: chemical, physiological and morphological characterization. Trends Neurosci. 1995;18(12):527–35.

    Article  CAS  PubMed  Google Scholar 

  257. Picconi B, Passino E, Sgobio C, Bonsi P, Barone I, Ghiglieri V, et al. Plastic and behavioral abnormalities in experimental Huntington’s disease: a crucial role for cholinergic interneurons. Neurobiol Dis. 2006;22(1):143–52.

    Article  CAS  PubMed  Google Scholar 

  258. Dragunow M. Human Brain Neuropharmacology: A Platform for Translational Neuroscience. Trends Pharmacol Sci. 2020;41(11):777–92.

    Article  CAS  PubMed  Google Scholar 

  259. Barker RA, Björklund A. Animal Models of Parkinson’s Disease: Are They Useful or Not? J Parkinsons Dis. 2020;10:1335–42.

    Article  PubMed  Google Scholar 

  260. Mishra MK, Beaty CA, Lesniak WG, Kambhampati SP, Zhang F, Wilson MA, et al. Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest. ACS Nano. 2014;8(3):2134–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Kannan S, Dai H, Navath RS, Balakrishnan B, Jyoti A, Janisse J, et al. Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med. 2012;4(130):130ra46.

  262. Zhang F, Mastorakos P, Mishra MK, Mangraviti A, Hwang L, Zhou J, et al. Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers. Biomaterials. 2015;52:507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Nance E, Porambo M, Zhang F, Mishra MK, Buelow M, Getzenberg R, et al. Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury. J Control Release. 2015;214:112–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Zhang F, Lin Y-A, Kannan S, Kannan RM. Targeting specific cells in the brain with nanomedicines for CNS therapies. J Control Release. 2016;240:212–26.

    Article  CAS  PubMed  Google Scholar 

  265. Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010;6(7):393–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Our collaborative efforts and the development of CNS-specific delivery strategies for nucleic acid therapeutics are supported by grants from the Massachusetts Life Sciences Center and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA

    Anisha D’Souza, Saeideh Nozohouri & Mansoor M. Amiji

  2. Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, 20115, USA

    Anisha D’Souza & Benjamin S. Bleier

  3. Department of Chemical Engineering, College of Engineering, Northeastern University, Boston, MA, 02115, USA

    Mansoor M. Amiji

Authors
  1. Anisha D’Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saeideh Nozohouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benjamin S. Bleier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mansoor M. Amiji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mansoor M. Amiji.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This invited manuscript is submitted for the thematic issue of the journal Pharmaceutical Research focusing on “Nucleic Acid Delivery” edited by Drs. Galen Shi and Zheng-Rong Lu.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

D’Souza, A., Nozohouri, S., Bleier, B.S. et al. CNS Delivery of Nucleic Acid Therapeutics: Beyond the Blood–Brain Barrier and Towards Specific Cellular Targeting. Pharm Res 40, 77–105 (2023). https://doi.org/10.1007/s11095-022-03433-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-022-03433-5

Keywords

Search

Navigation