Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

Chang Wang; Yonger Xue; Tamara Markovic; Haoyuan Li; Siyu Wang; Yichen Zhong; Shi Du; Yuebao Zhang; Xucheng Hou; Yang Yu; Zhengwei Liu; Meng Tian; Diana D. Kang; Leiming Wang; Kaiyuan Guo; Dinglingge Cao; Jingyue Yan; Binbin Deng; David W. McComb; Ramon E. Parsons; Angelica M. Minier-Toribio; Leanne M. Holt; Jiayi Pan; Alice Hashemi; Brian H. Kopell; Alexander W. Charney; Eric J. Nestler; Paul C. Peng; Yizhou Dong

doi:10.1038/s41563-024-02114-5

Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

Chang Wang, Yonger Xue, Tamara Markovic, Haoyuan Li, Siyu Wang, Yichen Zhong, Shi Du, Yuebao Zhang, Xucheng Hou, Yang Yu, Zhengwei Liu, Meng Tian, Diana D. Kang, Leiming Wang, Kaiyuan Guo, Dinglingge Cao, Jingyue Yan, Binbin Deng, David W. McComb, Ramon E. ParsonsAngelica M. Minier-Toribio, Leanne M. Holt, Jiayi Pan, Alice Hashemi, Brian H. Kopell, Alexander W. Charney, Eric J. Nestler, Paul C. Peng, Yizhou Dong

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood–brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids, and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery. Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples. Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.

Original language	English
Article number	e2116271119
Journal	Nature Materials
DOIs	https://doi.org/10.1038/s41563-024-02114-5
State	Accepted/In press - 2025

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Wang, C., Xue, Y., Markovic, T., Li, H., Wang, S., Zhong, Y., Du, S., Zhang, Y., Hou, X., Yu, Y., Liu, Z., Tian, M., Kang, D. D., Wang, L., Guo, K., Cao, D., Yan, J., Deng, B., McComb, D. W., ... Dong, Y. (Accepted/In press). Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. Nature Materials, Article e2116271119. https://doi.org/10.1038/s41563-024-02114-5

@article{91886764cefc463ba7dc7c98619aaebd,

title = "Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system",

abstract = "The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood–brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids, and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery. Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples. Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.",

author = "Chang Wang and Yonger Xue and Tamara Markovic and Haoyuan Li and Siyu Wang and Yichen Zhong and Shi Du and Yuebao Zhang and Xucheng Hou and Yang Yu and Zhengwei Liu and Meng Tian and Kang, {Diana D.} and Leiming Wang and Kaiyuan Guo and Dinglingge Cao and Jingyue Yan and Binbin Deng and McComb, {David W.} and Parsons, {Ramon E.} and Minier-Toribio, {Angelica M.} and Holt, {Leanne M.} and Jiayi Pan and Alice Hashemi and Kopell, {Brian H.} and Charney, {Alexander W.} and Nestler, {Eric J.} and Peng, {Paul C.} and Yizhou Dong",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2025.",

year = "2025",

doi = "10.1038/s41563-024-02114-5",

language = "English",

journal = "Nature Materials",

issn = "1476-1122",

publisher = "Nature Publishing Group",

}

Wang, C, Xue, Y, Markovic, T, Li, H, Wang, S, Zhong, Y, Du, S, Zhang, Y, Hou, X, Yu, Y, Liu, Z, Tian, M, Kang, DD, Wang, L, Guo, K, Cao, D, Yan, J, Deng, B, McComb, DW, Parsons, RE, Minier-Toribio, AM, Holt, LM, Pan, J, Hashemi, A, Kopell, BH , Charney, AW, Nestler, EJ, Peng, PC & Dong, Y 2025, 'Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system', Nature Materials. https://doi.org/10.1038/s41563-024-02114-5

TY - JOUR

T1 - Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

AU - Wang, Chang

AU - Xue, Yonger

AU - Markovic, Tamara

AU - Li, Haoyuan

AU - Wang, Siyu

AU - Zhong, Yichen

AU - Du, Shi

AU - Zhang, Yuebao

AU - Hou, Xucheng

AU - Yu, Yang

AU - Liu, Zhengwei

AU - Tian, Meng

AU - Kang, Diana D.

AU - Wang, Leiming

AU - Guo, Kaiyuan

AU - Cao, Dinglingge

AU - Yan, Jingyue

AU - Deng, Binbin

AU - McComb, David W.

AU - Parsons, Ramon E.

AU - Minier-Toribio, Angelica M.

AU - Holt, Leanne M.

AU - Pan, Jiayi

AU - Hashemi, Alice

AU - Kopell, Brian H.

AU - Charney, Alexander W.

AU - Nestler, Eric J.

AU - Peng, Paul C.

AU - Dong, Yizhou

PY - 2025

Y1 - 2025

N2 - The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood–brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids, and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery. Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples. Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.

AB - The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood–brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids, and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery. Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples. Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.

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U2 - 10.1038/s41563-024-02114-5

DO - 10.1038/s41563-024-02114-5

M3 - Article

AN - SCOPUS:85218191664

SN - 1476-1122

JO - Nature Materials

JF - Nature Materials

M1 - e2116271119

ER -

Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

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