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Chemical strategies for brain delivery of genomic therapy

Nature Reviews Chemistry volume 9, pages 841–854 (2025)Cite this article

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Abstract

Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.

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Fig. 1: LNP formulations.
Fig. 2: Chemical structures of lipids used in LNPs for brain delivery.
Fig. 3: Chemical structures of polymers used for brain delivery via intravenous injections.
Fig. 4: Chemical structures of polymers used for brain delivery via local administrations.
Fig. 5: Strategies for efficient delivery of oligonucleotides to the brain.

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References

  1. Park, H. J. & Friston, K. Structural and functional brain networks: from connections to cognition. Science 342, 1238411 (2013).

    Article  PubMed  Google Scholar 

  2. Sun, J. & Roy, S. Gene-based therapies for neurodegenerative diseases. Nat. Neurosci. 24, 297–311 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Feigin, V. L., Owolabi, M. O. & World Stroke Organization-Lancet Neurology Commission Stroke Collaboration Group Pragmatic solutions to reduce the global burden of stroke: a World Stroke Organization-Lancet Neurology Commission. Lancet Neurol. 22, 1160–1206 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Schaff, L. R. & Mellinghoff, I. K. Glioblastoma and other primary brain malignancies in adults: a review. JAMA 329, 574–587 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tabrizi, S. J., Flower, M. D., Ross, C. A. & Wild, E. J. Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat. Rev. Neurol. 16, 529–546 (2020).

    Article  PubMed  Google Scholar 

  7. Boros, B. D., Schoch, K. M., Kreple, C. J. & Miller, T. M. Antisense oligonucleotides for the study and treatment of ALS. Neurotherapeutics 19, 1145–1158 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sandweiss, A. J., Brandt, V. L. & Zoghbi, H. Y. Advances in understanding of Rett syndrome and MECP2 duplication syndrome: prospects for future therapies. Lancet Neurol. 19, 689–698 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Wang, Y., Zhao, Y., Bollas, A., Wang, Y. & Au, K. F. Nanopore sequencing technology, bioinformatics and applications. Nat. Biotechnol. 39, 1348–1365 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Roberts, T. C., Langer, R. & Wood, M. J. A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673–694 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Terstappen, G. C., Meyer, A. H., Bell, R. D. & Zhang, W. Strategies for delivering therapeutics across the blood-brain barrier. Nat. Rev. Drug Discov. 20, 362–383 (2021).

    Article  CAS  PubMed  Google Scholar 

  12. Shendure, J., Findlay, G. M. & Snyder, M. W. Genomic medicine — progress, pitfalls, and promise. Cell 177, 45–57 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miller, T. M. et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 387, 1099–1110 (2022).

    Article  CAS  PubMed  Google Scholar 

  14. Tai, C. H. et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol. Ther. 30, 509–518 (2022).

    Article  CAS  PubMed  Google Scholar 

  15. Nance, E., Pun, S. H., Saigal, R. & Sellers, D. L. Drug delivery to the central nervous system. Nat. Rev. Mater. 7, 314–331 (2022).

    Article  CAS  PubMed  Google Scholar 

  16. Huang, Q. et al. An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery. Science 384, 1220–1227 (2024).

    Article  CAS  PubMed  Google Scholar 

  17. Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao, J. et al. Gene therapy for CNS disorders: modalities, delivery and translational challenges. Nat. Rev. Neurosci. 25, 553–572 (2024).

    Article  CAS  PubMed  Google Scholar 

  20. Mendell, J. R. et al. Current clinical applications of in vivo gene therapy with AAVs. Mol. Ther. 29, 464–488 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. Challis, R. C. et al. Adeno-associated virus toolkit to target diverse brain cells. Annu. Rev. Neurosci. 45, 447–469 (2022).

    Article  CAS  PubMed  Google Scholar 

  22. Akinc, A. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 14, 1084–1087 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu, Y. et al. AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery. Nat. Commun. 15, 6305 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dahlman, J. E. et al. Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics. Proc. Natl Acad. Sci. USA 114, 2060–2065 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kuzminich, Y. et al. Lipid nanoparticles deliver mRNA to the blood–brain barrier. Nano Res. 17, 9126–9134 (2024).

    Article  CAS  Google Scholar 

  29. Han, E. L. et al. Predictive high-throughput platform for dual screening of mRNA lipid nanoparticle blood-brain barrier transfection and crossing. Nano Lett. 24, 1477–1486 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bergmann, S. et al. Blood-brain-barrier organoids for investigating the permeability of CNS therapeutics. Nat. Protoc. 13, 2827–2843 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dao, L. et al. Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids. Cell Stem Cell 31, 818–833.e11 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rhym, L. H., Manan, R. S., Koller, A., Stephanie, G. & Anderson, D. G. Peptide-encoding mRNA barcodes for the high-throughput in vivo screening of libraries of lipid nanoparticles for mRNA delivery. Nat. Biomed. Eng. 7, 901–910 (2023).

    Article  CAS  PubMed  Google Scholar 

  33. Ma, F. et al. Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection. Sci. Adv. 6, eabb4429 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ahmed, H. S. The multifaceted role of L-type amino acid transporter 1 at the blood-brain barrier: structural implications and therapeutic potential. Mol. Neurobiol. https://doi.org/10.1007/s12035-024-04506-9 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Pernot, P. et al. D-Serine diffusion through the blood-brain barrier: effect on D-serine compartmentalization and storage. Neurochem. Int. 60, 837–845 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Strobel, H. et al. Temozolomide and other alkylating agents in glioblastoma therapy. Biomedicines https://doi.org/10.3390/biomedicines7030069 (2019).

  37. Carbonaro, T. M. & Gatch, M. B. Neuropharmacology of N,N-dimethyltryptamine. Brain Res. Bull. 126, 74–88 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Drakontaeidi, A. & Pontiki, E. Multi-target-directed cinnamic acid hybrids targeting Alzheimer’s disease. Int. J. Mol. Sci. 25, 582 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cook, J. J. et al. Acute γ-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-β production to alternative APP fragments without amyloid-β rebound. J. Neurosci. 30, 6743–6750 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, C. et al. Blood-brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. Nat. Mater. https://doi.org/10.1038/s41563-024-02114-5 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Heller, E. A. et al. Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat. Neurosci. 17, 1720–1727 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cao, D. et al. Lipid nanoparticles for mRNA delivery in brain via systemic administration. Sci. Adv. 11, eadw0730 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nong, J. et al. Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke. Mol. Ther. 32, 1344–1358 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Han, E. L. et al. Peptide-functionalized lipid nanoparticles for targeted systemic mRNA delivery to the brain. Nano Lett. https://doi.org/10.1021/acs.nanolett.4c05186 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li, W. et al. BBB pathophysiology-independent delivery of siRNA in traumatic brain injury. Sci. Adv. 7, eabd6889 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Brown, D. W. et al. Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles. Cell 187, 5357–5375.e24 (2024).

    Article  CAS  PubMed  Google Scholar 

  47. Nabhan, J. F. 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. 6, 20019 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rosenblum, D. et al. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Sci. Adv. 6, eabc9450 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dhaliwal, H. K., Fan, Y., Kim, J. & Amiji, M. M. Intranasal delivery and transfection of mRNA therapeutics in the brain using cationic liposomes. Mol. Pharm. 17, 1996–2005 (2020).

    Article  CAS  PubMed  Google Scholar 

  50. Lao, Y. H. et al. Focused ultrasound-mediated brain genome editing. Proc. Natl Acad. Sci. USA 120, e2302910120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ogawa, K. et al. Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain. J. Control. Release 348, 34–41 (2022).

    Article  CAS  PubMed  Google Scholar 

  52. Zhou, X., Smith, Q. R. & Liu, X. Brain penetrating peptides and peptide-drug conjugates to overcome the blood-brain barrier and target CNS diseases. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 13, e1695 (2021).

    Article  PubMed  Google Scholar 

  53. Ribovski, L., Hamelmann, N. M. & Paulusse, J. M. J. Polymeric nanoparticles properties and brain delivery. Pharmaceutics 13, 2045 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Huang, S. et al. Dual targeting effect of Angiopep-2-modified, DNA-loaded nanoparticles for glioma. Biomaterials 32, 6832–6838 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Gao, S. et al. A non-viral suicide gene delivery system traversing the blood brain barrier for non-invasive glioma targeting treatment. J. Control. Release 243, 357–369 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Zou, Y. et al. Blood-brain barrier-penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy. Sci. Adv. 8, eabm8011 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kurzrock, R. et al. Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of Angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. Mol. Cancer Ther. 11, 308–316 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Son, S. et al. RVG peptide tethered bioreducible polyethylenimine for gene delivery to brain. J. Control. Release 155, 18–25 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Liu, Y. et al. Brain-targeting gene delivery and cellular internalization mechanisms for modified rabies virus glycoprotein RVG29 nanoparticles. Biomaterials 30, 4195–4202 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Wang, P. et al. Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of Alzheimer’s disease. J. Control. Release 279, 220–233 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Suarez, V. M., Vispo, N. S. & Ramos, O. S. Application of the phage display technology for the development of peptide-mediated drug delivery systems through the blood-brain barrier. Curr. Pharm. Biotechnol. 22, 1394–1403 (2021).

    Article  CAS  PubMed  Google Scholar 

  62. Motone, K. et al. Multi-pass, single-molecule nanopore reading of long protein strands. Nature 633, 662–669 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Huang, R., Ke, W., Liu, Y., Jiang, C. & Pei, Y. The use of lactoferrin as a ligand for targeting the polyamidoamine-based gene delivery system to the brain. Biomaterials 29, 238–246 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Huang, R. et al. Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model. J. Neurol. Sci. 290, 123–130 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Devraj, K. et al. GLUT-1 glucose transporters in the blood-brain barrier: differential phosphorylation. J. Neurosci. Res. 89, 1913–1925 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Anraku, Y. et al. Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain. Nat. Commun. 8, 1001 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Suzuki, K. et al. Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors. J. Control. Release 301, 28–41 (2019).

    Article  CAS  PubMed  Google Scholar 

  68. Min, H. S. et al. Systemic brain delivery of antisense oligonucleotides across the blood-brain barrier with a glucose-coated polymeric nanocarrier. Angew. Chem. Int. Ed. 59, 8173–8180 (2020).

    Article  CAS  Google Scholar 

  69. Kim, M. et al. Delivery of self-replicating messenger RNA into the brain for the treatment of ischemic stroke. J. Control. Release 350, 471–485 (2022).

    Article  CAS  PubMed  Google Scholar 

  70. Oh, J., Lee, M. S., Jeong, J. H. & Lee, M. Deoxycholic acid-conjugated polyethylenimine for delivery of heme oxygenase-1 gene in rat ischemic stroke model. J. Pharm. Sci. 106, 3524–3532 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Cheng, Y. et al. Nano-sized sunflower polycations as effective gene transfer vehicles. Small 12, 2750–2758 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sadeqi Nezhad, M. Poly (beta-amino ester) as an in vivo nanocarrier for therapeutic nucleic acids. Biotechnol. Bioeng. 120, 95–113 (2023).

    Article  CAS  PubMed  Google Scholar 

  73. Liu, Y., Li, Y., Keskin, D. & Shi, L. Poly(beta-amino esters): synthesis, formulations, and their biomedical applications. Adv. Healthc. Mater. 8, e1801359 (2019).

    Article  PubMed  Google Scholar 

  74. Guerrero-Cazares, H. et al. Biodegradable polymeric nanoparticles show high efficacy and specificity at DNA delivery to human glioblastoma in vitro and in vivo. ACS Nano 8, 5141–5153 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chen, Q. et al. Poly(beta-amino ester)-based nanoparticles enable nonviral delivery of base editors for targeted tumor gene editing. Biomacromolecules 23, 2116–2125 (2022).

    Article  CAS  PubMed  Google Scholar 

  76. Li, H. et al. Engineering brain-derived neurotrophic factor mRNA delivery for the treatment of Alzheimer’s disease. Chem. Eng. J. 466, 143152 (2023).

    Article  CAS  Google Scholar 

  77. Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Barker, S. J. et al. Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier. Sci. Transl. Med. 16, eadi2245 (2024).

    Article  CAS  PubMed  Google Scholar 

  79. Nagata, T. et al. Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood-brain barrier and knock down genes in the rodent CNS. Nat. Biotechnol. 39, 1529–1536 (2021).

    Article  CAS  PubMed  Google Scholar 

  80. Pardridge, W. M. Drug transport across the blood-brain barrier. J. Cereb. Blood Flow Metab. 32, 1959–1972 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wang, C. et al. Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02487-7 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Balwani, M. et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N. Engl. J. Med. 382, 2289–2301 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, Y. et al. Overcoming the blood-brain barrier for gene therapy via systemic administration of GSH-responsive silica nanocapsules. Adv. Mater. 35, e2208018 (2023).

    Article  PubMed  Google Scholar 

  85. Brown, K. M. et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat. Biotechnol. 40, 1500–1508 (2022).

    Article  CAS  PubMed  Google Scholar 

  86. Alterman, J. F. et al. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat. Biotechnol. 37, 884–894 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yamada, K. et al. Enhancing siRNA efficacy in vivo with extended nucleic acid backbones. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02336-7 (2024).

    Article  PubMed  Google Scholar 

  88. Hammond, S. M. et al. Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy. JCI Insight 7, e154142 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Chiriboga, C. A. Pharmacotherapy for spinal muscular atrophy in babies and children: a review of approved and experimental therapies. Paediatr. Drugs 24, 585–602 (2022).

    Article  PubMed  Google Scholar 

  90. Heidari, R., Assadollahi, V., Khosravian, P., Mirzaei, S. A. & Elahian, F. Engineered mesoporous silica nanoparticles, new insight nanoplatforms into effective cancer gene therapy. Int. J. Biol. Macromol. 253, 127060 (2023).

    Article  CAS  PubMed  Google Scholar 

  91. Gu, W. et al. Extracellular vesicles incorporating retrovirus-like capsids for the enhanced packaging and systemic delivery of mRNA into neurons. Nat. Biomed. Eng. 8, 415–426 (2024).

    Article  CAS  PubMed  Google Scholar 

  92. Yang, Z. et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat. Biomed. Eng. 4, 69–83 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Hamilton, P. J. & Nestler, E. J. Epigenetics and addiction. Curr. Opin. Neurobiol. 59, 128–136 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kronman, H. et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nat. Neurosci. 24, 667–676 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nestler, E. J. The biology of addiction. Sci. Signal. 18, eadq0031 (2025).

    Article  CAS  PubMed  Google Scholar 

  96. Nestler, E. J. Epigenetic mechanisms of depression. JAMA Psychiatry 71, 454–456 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Duncan, C. N. et al. Hematologic cancer after gene therapy for cerebral adrenoleukodystrophy. N. Engl. J. Med. 391, 1287–1301 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mendell, J. R. et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann. Neurol. 74, 637–647 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Benson, M. D. et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 22–31 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Frank, D. E. et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology 94, e2270–e2282 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Day, J. W. et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 20, 284–293 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Wagner, K. R. et al. Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: a randomized, double-blind, placebo-controlled, dose-titration trial. Muscle Nerve 64, 285–292 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Eichler, F. et al. Lentiviral gene therapy for cerebral adrenoleukodystrophy. N. Engl. J. Med. 391, 1302–1312 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Fontana, M. et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2409134 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Zaidman, C. M. et al. Delandistrogene moxeparvovec gene therapy in ambulatory patients (aged ≥4 to <8 years) with Duchenne muscular dystrophy: 1-year interim results from study SRP-9001-103 (ENDEAVOR). Ann. Neurol. 94, 955–968 (2023).

    Article  CAS  PubMed  Google Scholar 

  106. Coelho, T. et al. Eplontersen for hereditary transthyretin amyloidosis with polyneuropathy. JAMA 330, 1448–1458 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fumagalli, F. et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet 399, 372–383 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Glassman, P. M. et al. Targeting drug delivery in the vascular system: focus on endothelium. Adv. Drug Deliv. Rev. 157, 96–117 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sempere, A. P., Berenguer-Ruiz, L., Lezcano-Rodas, M., Mira-Berenguer, F. & Waez, M. [Lumbar puncture: its indications, contraindications, complications and technique]. Rev. Neurol. 45, 433–436 (2007).

    CAS  PubMed  Google Scholar 

  110. Nau, R., Blei, C. & Eiffert, H. Intrathecal antibacterial and antifungal therapies. Clin. Microbiol. Rev. 33, e00190-19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Ericson, T., Singla, P. & Kohan, L. Intrathecal pumps. Phys. Med. Rehabil. Clin. N. Am. 33, 409–424 (2022).

    Article  PubMed  Google Scholar 

  112. Nagel, S. J. et al. Intrathecal therapeutics: device design, access methods, and complication mitigation. Neuromodulation 21, 625–640 (2018).

    Article  PubMed  Google Scholar 

  113. Magill, S. T., Choy, W., Nguyen, M. P. & McDermott, M. W. Ommaya reservoir insertion: a technical note. Cureus 12, e7731 (2020).

    PubMed  PubMed Central  Google Scholar 

  114. Kaplitt, M. G. et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet 369, 2097–2105 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. van Putten, E. H. P. et al. Convection enhanced delivery of the oncolytic adenovirus Delta24-RGD in patients with recurrent GBM: a phase I clinical trial including correlative studies. Clin. Cancer Res. 28, 1572–1585 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Keller, L. A., Merkel, O. & Popp, A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv. Transl. Res. 12, 735–757 (2022).

    Article  PubMed  Google Scholar 

  117. Duong, V. A., Nguyen, T. T. & Maeng, H. J. Recent advances in intranasal liposomes for drug, gene, and vaccine delivery. Pharmaceutics 15, 207 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Rezai, A. R. et al. Ultrasound blood-brain barrier opening and Aducanumab in Alzheimer’s disease. N. Engl. J. Med. 390, 55–62 (2024).

    Article  CAS  PubMed  Google Scholar 

  119. Kwak, G. et al. Brain nucleic acid delivery and genome editing via focused ultrasound-mediated blood-brain barrier opening and long-circulating nanoparticles. ACS Nano 18, 24139–24153 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Y.D. acknowledges the support from the Maximizing Investigators’ Research Award R35GM144117 from the National Institute of General Medical Sciences and funds from the Icahn School of Medicine at Mount Sinai.

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Authors and Affiliations

  1. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Haoyuan Li, Changyue Yu & Yizhou Dong

  2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Haoyuan Li, Changyue Yu & Yizhou Dong

  3. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Haoyuan Li, Changyue Yu & Yizhou Dong

  4. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Haoyuan Li, Changyue Yu & Yizhou Dong

  5. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Haoyuan Li, Changyue Yu & Yizhou Dong

  6. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Haoyuan Li, Changyue Yu & Yizhou Dong

  7. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Haoyuan Li, Changyue Yu, Tamara Markovic, Eric J. Nestler & Yizhou Dong

  8. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Tamara Markovic & Eric J. Nestler

Authors
  1. Haoyuan Li
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  2. Changyue Yu
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  3. Tamara Markovic
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  4. Eric J. Nestler
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  5. Yizhou Dong
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Contributions

Y.D. and E.J.N. conceived the concept of the article. H.L. and Y.D. contributed to the draft writing. C.Y. contributed to the figures. E.J.N. and T.M. edited the manuscript. Y.D. and E.J.N. reviewed the manuscript before submission.

Corresponding authors

Correspondence to Eric J. Nestler or Yizhou Dong.

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Competing interests

Y.D. is a cofounder and holds equity in Immunanoengineering Therapeutics. The other authors declare no competing interests.

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Nature Reviews Chemistry thanks Michael Mitchell and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Li, H., Yu, C., Markovic, T. et al. Chemical strategies for brain delivery of genomic therapy. Nat Rev Chem 9, 841–854 (2025). https://doi.org/10.1038/s41570-025-00770-y

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