Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system

Chang Wang^#^{1

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7}, Siyu Wang^#^{1

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7}, Yonger Xue^{1

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7}, Yichen Zhong^{1

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7}, Haoyuan Li^{1

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7}, Xucheng Hou^{1

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7}, Diana D Kang^{1

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8}, Zhengwei Liu^{1

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7}, Meng Tian^{1

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7}, Leiming Wang^{1

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7}, Dinglingge Cao^{1

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7}, Yang Yu⁸, Jayce Liu⁸, Xiaolin Cheng^{8

9}, Tamara Markovic^{6

10}, Alice Hashemi¹¹, Brian H Kopell¹¹, Alexander W Charney¹¹, Eric J Nestler^{12

13}, Yizhou Dong^{14

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20}

Affiliations

¹ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ College of Pharmacy, The Ohio State University, Columbus, Columbus, OH, USA.
⁹ Translational Data Analytics Institute, The Ohio State University, Columbus, OH, USA.
¹⁰ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Charles Bronfman Institute for Personalized Medicine, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eric.nestler@mssm.edu.
¹³ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eric.nestler@mssm.edu.
¹⁴ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁵ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁶ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁷ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁸ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁹ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
²⁰ Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.

^# Contributed equally.

PMID: 39587229
DOI: 10.1038/s41587-024-02487-7

Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system

Chang Wang et al. Nat Biotechnol. 2024.

. 2024 Nov 25.

doi: 10.1038/s41587-024-02487-7. Online ahead of print.

Authors

Affiliations

¹ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ College of Pharmacy, The Ohio State University, Columbus, Columbus, OH, USA.
⁹ Translational Data Analytics Institute, The Ohio State University, Columbus, OH, USA.
¹⁰ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Charles Bronfman Institute for Personalized Medicine, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eric.nestler@mssm.edu.
¹³ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eric.nestler@mssm.edu.
¹⁴ Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁵ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁶ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁷ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁸ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
¹⁹ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
²⁰ Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.

^# Contributed equally.

PMID: 39587229
DOI: 10.1038/s41587-024-02487-7

Erratum in

Author Correction: Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.
Wang C, Wang S, Xue Y, Zhong Y, Li H, Hou X, Kang DD, Liu Z, Tian M, Wang L, Cao D, Yu Y, Liu J, Cheng X, Markovic T, Hashemi A, Kopell BH, Charney AW, Nestler EJ, Dong Y. Wang C, et al. Nat Biotechnol. 2025 Mar 4. doi: 10.1038/s41587-025-02601-3. Online ahead of print. Nat Biotechnol. 2025. PMID: 40038437 No abstract available.

Abstract

Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood-brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10-oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an amyotrophic lateral sclerosis mouse model.

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Conflict of interest statement

Competing interests: Y.D. is a scientific advisor for Arbor Biotechnologies, siRNAgen Therapeutics and Moonwalk Biosciences. Y.D. is a cofounder and holds equity in Immunanoengineering Therapeutics. The other authors declare no competing interests.

References

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1. Juliano, R. L., Ming, X. & Nakagawa, O. The chemistry and biology of oligonucleotide conjugates. Acc. Chem. Res. 45, 1067–1076 (2012). - PubMed - PMC - DOI
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1. Roberts, T. C., Langer, R. & Wood, M. J. A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673–694 (2020). - PubMed - PMC - DOI

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Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system

Affiliations

Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

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