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Close the cancer–immunity cycle by integrating lipid nanoparticle–mRNA formulations and dendritic cell therapy

Nature Nanotechnology volume 18, pages 1364–1374 (2023)Cite this article

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Abstract

Effective cancer immunotherapy is usually blocked by immunosuppressive factors in the tumour microenvironment, resulting in tumour promotion, metastasis and recurrence. Here we combine lipid nanoparticle–mRNA formulations and dendritic cell therapy (named CATCH) to boost the cancer–immunity cycle via progressive steps to overcome the immunosuppressive tumour microenvironment. Multiple types of sugar-alcohol-derived lipid nanoparticles are conceived to modulate the cancer–immunity cycle. First, one type of lipid nanoparticle containing CD40 ligand mRNA induces robust immunogenic cell death in tumoural tissues, leading to the release of tumour-associated antigens and the expression of CD40 ligand. Next, dendritic cells engineered by another type of lipid nanoparticle encapsulating CD40 mRNA are adoptively transferred, which are then activated by the CD40 ligand molecules in tumoural tissues. This promotes the secretion of multiple cytokines and chemokines, and the upregulation of co-stimulatory molecules on dendritic cells, which are crucial for reprogramming the tumour microenvironment and priming the T-cell responses. After dendritic cells present tumour-associated antigens to T cells, all the above stepwise events contribute to boosting a potent tumour-specific T-cell immunity that eradicates established tumours, suppresses distal lesions and prevents tumour rechallenge.

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Fig. 1: Chemical synthesis of sugar-alcohol-derived ionizable lipids.
Fig. 2: Screening, optimization and characterization of LNP–mRNA formulations.
Fig. 3: DC activation, LNP-induced ICD and therapeutic effects on primary tumour and rechallenged tumour.
Fig. 4: Therapeutic effects on two tumour or immune cell depletion models, and dynamic expression of cytokines and chemokines in tumoural tissues and blood.
Fig. 5: Changes in immune cell infiltration, memory T cells and mRNA transcripts.
Fig. 6: Applicability of CATCH treatment regimen in other tumour models and human-derived cells.

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Data availability

Source data are provided with this paper. Additional materials for this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Cryo-TEM imaging was performed at the Center for Electron Microscopy and Analysis (CEMAS) at The Ohio State University. The Genomics Shared Resource performed the nCounter NanoString analysis for this study with part support from the National Cancer Institute (grant P30 CA016058). Y.D. acknowledges support from the Maximizing Investigators’ Research Award R35GM144117 from the National Institute of General Medical Sciences as well as the funding from the Icahn School of Medicine at Mount Sinai. X.H. and J.Y. acknowledge support from the Professor Sylvan G. Frank Graduate Fellowship.

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Author notes

  1. These authors contributed equally: Yuebao Zhang, Xucheng Hou, Shi Du.

Authors and Affiliations

  1. Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Yuebao Zhang, Xucheng Hou, Shi Du, Yonger Xue, Jingyue Yan, Diana D. Kang, Yichen Zhong, Chang Wang & Yizhou Dong

  2. Icahn Genomics Institute, Precision Immunology Institute, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Xucheng Hou, Shi Du, Yonger Xue, Jingyue Yan, Diana D. Kang, Yichen Zhong, Chang Wang & Yizhou Dong

  3. Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, USA

    Binbin Deng & David W. McComb

  4. Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA

    David W. McComb

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Contributions

Y. Zhang, X.H. and S.D. conceived the work, performed the experiments, analysed the data and wrote the paper. Y.X., J.Y., D.D.K., Y. Zhong and C.W. contributed to the mRNA synthesis, LNP characterization and flow cytometry assays. B.D. and D.W.M. contributed to the cryo-TEM imaging. Y.D. conceived and supervised the project and wrote the paper. The final paper was edited and approved by all authors.

Corresponding author

Correspondence to Yizhou Dong.

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Competing interests

Y.D. is a scientific advisory board member of Oncorus Inc., Arbor Biotechnologies and FL85. The other authors declare no competing interests.

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Zhang, Y., Hou, X., Du, S. et al. Close the cancer–immunity cycle by integrating lipid nanoparticle–mRNA formulations and dendritic cell therapy. Nat. Nanotechnol. 18, 1364–1374 (2023). https://doi.org/10.1038/s41565-023-01453-9

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