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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

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CONTENT BEING VIEWED BY OTHERS UNIVERSAL STING MIMIC BOOSTS ANTITUMOUR IMMUNITY VIA PREFERENTIAL ACTIVATION OF TUMOUR CONTROL SIGNALLING PATHWAYS Article 13 March 2024 CHEMICALLY PROGRAMMED

STING-ACTIVATING NANO-LIPOSOMAL VESICLES IMPROVE ANTICANCER IMMUNITY Article Open access 31 July 2023 ZINC CYCLIC DI-AMP NANOPARTICLES TARGET AND SUPPRESS TUMOURS VIA ENDOTHELIAL STING

ACTIVATION AND TUMOUR-ASSOCIATED MACROPHAGE REINVIGORATION Article 27 October 2022 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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Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * 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 * Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA Pere Dosta, Alexander M. Cryer, Michelle Z. Dion, Núria Puigmal 

& Natalie Artzi * Harvard-MIT Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA, USA Michelle Z. Dion * 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 * Biodevek, Cambridge, MA, USA Gonzalo Muñoz Taboada Authors * Pere Dosta View author publications You can also search for this author inPubMed Google

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Artzi View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING

AUTHORS Correspondence to Pere Dosta or Natalie Artzi. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature

Nanotechnology_ thanks Jordan Green, Jason Luke and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer

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discussion and uncropped scans of all blots and gels. REPORTING SUMMARY SOURCE DATA SOURCE DATA FIG. 1 Raw data. SOURCE DATA FIG. 2 Raw data. SOURCE DATA FIG. 3 Raw data. SOURCE DATA FIG. 4

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such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation *

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