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

Nat Biomed Eng. 2023 Dec 11. doi: 10.1038/s41551-023-01131-0. Online ahead of print.

Authors

Yining Zhu^{1

2

3}, Jingyao Ma^{2

3

4

5}, Ruochen Shen^{1

2

3}, Jinghan Lin^{1

2

3}, Shuyi Li^{2

3

6

7}, Xiaoya Lu^{2

3

5}, Jessica L Stelzel^{1

2

3}, Jiayuan Kong^{2

3

5}, Leonardo Cheng^{1

2

3}, Ivan Vuong^{1

2

3}, Zhi-Cheng Yao^{2

3

5}, Christine Wei^{1

2

3}, Nicole M Korinetz^{2

3

4}, Wu Han Toh^{2

3

8

9}, Joseph Choy^{2

3

5}, Rebekah A Reynolds^{10

11}, Melanie J Shears^{10

11}, Won June Cho^{2

4}, Natalie K Livingston^{1

2

3

6

7}, Gregory P Howard^{1

2

3}, Yizong Hu^{1

2

3}, Stephany Y Tzeng^{1

2

3}, Donald J Zack¹², Jordan J Green^{1

2

3

4

5

12

13}, Lei Zheng¹³, Joshua C Doloff^{1

2

3

5

13}, Jonathan P Schneck^{2

6

7

14}, Sashank K Reddy^{1

2

15}, Sean C Murphy^{16

17

18}, Hai-Quan Mao^{19

20

21

22}

Affiliations

¹ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
³ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁶ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
⁹ Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
¹¹ Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA.
¹² Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. murphysc@uw.edu.
¹⁷ Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA. murphysc@uw.edu.
¹⁸ Department of Microbiology, University of Washington, Seattle, WA, USA. murphysc@uw.edu.
¹⁹ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. hmao@jhu.edu.
²⁰ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA. hmao@jhu.edu.
²¹ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. hmao@jhu.edu.
²² Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA. hmao@jhu.edu.

PMID: 38082180
DOI: 10.1038/s41551-023-01131-0

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.

Abstract

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