Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity

Yining Zhu; Jingyao Ma; Ruochen Shen; Jinghan Lin; Shuyi Li; Xiaoya Lu; Jessica L. Stelzel; Jiayuan Kong; Leonardo Cheng; Ivan Vuong; Zhi Cheng Yao; Christine Wei; Nicole M. Korinetz; Wu Han Toh; Joseph Choy; Rebekah A. Reynolds; Melanie J. Shears; Won June Cho; Natalie K. Livingston; Gregory P. Howard; Yizong Hu; Stephany Y. Tzeng; Donald J. Zack; Jordan J. Green; Lei Zheng; Joshua C. Doloff; Jonathan P. Schneck; Sashank K. Reddy; Sean C. Murphy; Hai Quan Mao

doi:10.1038/s41551-023-01131-0

Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity

Yining Zhu, Jingyao Ma, Ruochen Shen, Jinghan Lin, Shuyi Li, Xiaoya Lu, Jessica L. Stelzel, Jiayuan Kong, Leonardo Cheng, Ivan Vuong, Zhi Cheng Yao, Christine Wei, Nicole M. Korinetz, Wu Han Toh, Joseph Choy, Rebekah A. Reynolds, Melanie J. Shears, Won June Cho, Natalie K. Livingston, Gregory P. HowardYizong Hu, Stephany Y. Tzeng, Donald J. Zack, Jordan J. Green, Lei Zheng, Joshua C. Doloff, Jonathan P. Schneck, Sashank K. Reddy, Sean C. Murphy, Hai Quan Mao

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

63 Scopus citations

Abstract

Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.

Original language	English (US)
Pages (from-to)	544-560
Number of pages	17
Journal	Nature Biomedical Engineering
Volume	8
Issue number	5
DOIs	https://doi.org/10.1038/s41551-023-01131-0
State	Published - May 2024
Externally published	Yes

ASJC Scopus subject areas

Biotechnology
Bioengineering
Medicine (miscellaneous)
Biomedical Engineering
Computer Science Applications

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10.1038/s41551-023-01131-0

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Zhu, Y., Ma, J., Shen, R., Lin, J., Li, S., Lu, X., Stelzel, J. L., Kong, J., Cheng, L., Vuong, I., Yao, Z. C., Wei, C., Korinetz, N. M., Toh, W. H., Choy, J., Reynolds, R. A., Shears, M. J., Cho, W. J., Livingston, N. K., ... Mao, H. Q. (2024). Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity. Nature Biomedical Engineering, 8(5), 544-560. https://doi.org/10.1038/s41551-023-01131-0

Zhu, Y, Ma, J, Shen, R, Lin, J, Li, S, Lu, X, Stelzel, JL, Kong, J, Cheng, L, Vuong, I, Yao, ZC, Wei, C, Korinetz, NM, Toh, WH, Choy, J, Reynolds, RA, Shears, MJ, Cho, WJ, Livingston, NK, Howard, GP, Hu, Y, Tzeng, SY, Zack, DJ, Green, JJ, Zheng, L, Doloff, JC, Schneck, JP, Reddy, SK, Murphy, SC & Mao, HQ 2024, 'Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity', Nature Biomedical Engineering, vol. 8, no. 5, pp. 544-560. https://doi.org/10.1038/s41551-023-01131-0

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title = "Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity",

abstract = "Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.",

author = "Yining Zhu and Jingyao Ma and Ruochen Shen and Jinghan Lin and Shuyi Li and Xiaoya Lu and Stelzel, \{Jessica L.\} and Jiayuan Kong and Leonardo Cheng and Ivan Vuong and Yao, \{Zhi Cheng\} and Christine Wei and Korinetz, \{Nicole M.\} and Toh, \{Wu Han\} and Joseph Choy and Reynolds, \{Rebekah A.\} and Shears, \{Melanie J.\} and Cho, \{Won June\} and Livingston, \{Natalie K.\} and Howard, \{Gregory P.\} and Yizong Hu and Tzeng, \{Stephany Y.\} and Zack, \{Donald J.\} and Green, \{Jordan J.\} and Lei Zheng and Doloff, \{Joshua C.\} and Schneck, \{Jonathan P.\} and Reddy, \{Sashank K.\} and Murphy, \{Sean C.\} and Mao, \{Hai Quan\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2023.",

year = "2024",

month = may,

doi = "10.1038/s41551-023-01131-0",

language = "English (US)",

volume = "8",

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T1 - Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity

AU - Zhu, Yining

AU - Ma, Jingyao

AU - Shen, Ruochen

AU - Lin, Jinghan

AU - Li, Shuyi

AU - Lu, Xiaoya

AU - Stelzel, Jessica L.

AU - Kong, Jiayuan

AU - Cheng, Leonardo

AU - Vuong, Ivan

AU - Yao, Zhi Cheng

AU - Wei, Christine

AU - Korinetz, Nicole M.

AU - Toh, Wu Han

AU - Choy, Joseph

AU - Reynolds, Rebekah A.

AU - Shears, Melanie J.

AU - Cho, Won June

AU - Livingston, Natalie K.

AU - Howard, Gregory P.

AU - Hu, Yizong

AU - Tzeng, Stephany Y.

AU - Zack, Donald J.

AU - Green, Jordan J.

AU - Zheng, Lei

AU - Doloff, Joshua C.

AU - Schneck, Jonathan P.

AU - Reddy, Sashank K.

AU - Murphy, Sean C.

AU - Mao, Hai Quan

PY - 2024/5

Y1 - 2024/5

N2 - Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.

AB - Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.

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ER -

Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity

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