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

Pere Dosta, Alexander M. Cryer, Michelle Z. Dion, Tsubasa Shiraishi, Steven P. Langston, David Lok, Jianing Wang, Sean Harrison, Tiquella Hatten, Michelle L. Ganno, Vicky A. Appleman, Gonzalo Muñoz Taboada, Núria Puigmal, Shiran Ferber, Santhosh Kalash, Michaela Prado, Alma L. Rodríguez, Walid S. Kamoun, Adnan O. Abu-Yousif, Natalie Artzi

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11 Cites (Scopus)

Resum

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.

Idioma originalAnglès
Pàgines (de-a)1351-1363
Nombre de pàgines13
RevistaNature Nanotechnology
Volum18
Número11
DOIs
Estat de la publicacióPublicada - de nov. 2023
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