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

Chang Wang; Siyu Wang; Yonger Xue; Yichen Zhong; Haoyuan Li; Xucheng Hou; Diana D Kang; Zhengwei Liu; Meng Tian; Leiming Wang; Dinglingge Cao; Yang Yu; Jayce Liu; Xiaolin Cheng; Tamara Markovic; Alice Hashemi; Brian H Kopell; Alexander W Charney; Eric J Nestler; Yizhou Dong

doi:10.1038/s41587-024-02487-7

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

Nat Biotechnol. 2024 Nov 25. doi: 10.1038/s41587-024-02487-7. Online ahead of print.

Authors

Chang Wang^#^{1

2

3

4

5

6

7}, Siyu Wang^#^{1

2

3

4

5

6

7}, Yonger Xue^{1

2

3

4

5

6

7}, Yichen Zhong^{1

2

3

4

5

6

7}, Haoyuan Li^{1

2

3

4

5

6

7}, Xucheng Hou^{1

2

3

4

5

6

7}, Diana D Kang^{1

2

3

4

5

6

7

8}, Zhengwei Liu^{1

2

3

4

5

6

7}, Meng Tian^{1

2

3

4

5

6

7}, Leiming Wang^{1

2

3

4

5

6

7}, Dinglingge Cao^{1

2

3

4

5

6

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

15

16

17

18

19

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

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.