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Investigation of the enhanced antitumour potency of STING agonist after conjugation to polymer nanoparticles

Nature Nanotechnology volume 18, pages 1351–1363 (2023)Cite this article

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Abstract

Intravenously administered cyclic dinucleotides and other STING agonists are hampered by low cellular uptake and poor circulatory half-life. Here we report the covalent conjugation of cyclic dinucleotides to poly(β-amino ester) nanoparticles through a cathepsin-sensitive linker. This is shown to increase stability and loading, thereby expanding the therapeutic window in multiple syngeneic tumour models, enabling the study of how the long-term fate of the nanoparticles affects the immune response. In a melanoma mouse model, primary tumour clearance depends on the STING signalling by host cells—rather than cancer cells—and immune memory depends on the spleen. The cancer cells act as a depot for the nanoparticles, releasing them over time to activate nearby immune cells to control tumour growth. Collectively, this work highlights the importance of nanoparticle structure and nano-biointeractions in controlling immunotherapy efficacy.

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Fig. 1: Schematic, optimization and characterization of CDN-NP formulations.
Fig. 2: CDN-NP distribution, cell internalization and cytokine activation after i.v. administration.
Fig. 3: CDN-NPs improve therapeutic outcome of CDN and synergize with ICB.
Fig. 4: CDN-NPs activate innate and adaptive antitumour immune responses.
Fig. 5: Host cell activation following STING delivery is sufficient to promote antitumour immunity.
Fig. 6: Cancer cells serve as a CDN-NP reservoir, releasing the CDN-NPs into neighbouring immune cells and activating them.

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Data availability

All data generated or analysed that support the findings of this study are available within this Article and its Supplementary Information. All raw data from this study are available from the corresponding author upon request. Source data are provided with this paper.

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Acknowledgements

We are grateful for the support and funding of Takeda Pharmaceuticals. We thank the Hale Building for Transformative Medicine, the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) and at Takeda Boston for the assistance with animal housing. We also thank A. M. Hayward and P. Chamberlain from the Department of Comparative Medicine at MIT for animal assistance, G. Paradis for FACS assistance with Cancer Center Support (FACS core) and K. Cormier for histology assistance.

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Authors and Affiliations

  1. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Pere Dosta, Alexander M. Cryer, Michelle Z. Dion, Núria Puigmal, Shiran Ferber, Santhosh Kalash, Michaela Prado, Alma L. Rodríguez & Natalie Artzi

  2. Department of Medicine, Division of Engineering in Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Pere Dosta, Alexander M. Cryer, Michelle Z. Dion, Núria Puigmal, Shiran Ferber, Santhosh Kalash, Michaela Prado, Alma L. Rodríguez & Natalie Artzi

  3. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Pere Dosta, Alexander M. Cryer, Michelle Z. Dion, Núria Puigmal & Natalie Artzi

  4. Harvard-MIT Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Michelle Z. Dion

  5. Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA

    Tsubasa Shiraishi, Steven P. Langston, David Lok, Jianing Wang, Sean Harrison, Tiquella Hatten, Michelle L. Ganno, Vicky A. Appleman, Walid S. Kamoun & Adnan O. Abu-Yousif

  6. Biodevek, Cambridge, MA, USA

    Gonzalo Muñoz Taboada

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Contributions

P.D., A.O.A.-Y. and N.A. conceived the study. P.D. designed the experiments. S.P.L., D.L., J.W. and S.H. performed the ML-317 synthesis and quantification. P.D., A.M.C., M.Z.D., D.L., J.W., S.H., G.M.T., N.P., S.F., M.P. and A.L.R. performed the in vitro experiments. P.D., A.M.C., S.K., T.H., M.L.G. and V.A.A. performed the in vivo experiments. P.D., A.M.C., M.Z.D. and N.A. drafted and finalized the manuscript with input from all other authors.

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Correspondence to Pere Dosta or Natalie Artzi.

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Supplementary Figs. 1–51, discussion and uncropped scans of all blots and gels.

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Dosta, P., Cryer, A.M., Dion, M.Z. et al. Investigation of the enhanced antitumour potency of STING agonist after conjugation to polymer nanoparticles. Nat. Nanotechnol. 18, 1351–1363 (2023). https://doi.org/10.1038/s41565-023-01447-7

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