Investigation of the enhanced antitumour potency of STING agonist after conjugation to polymer nanoparticles
Menée à l'aide de lignées cellulaires et d'un modèle murin de mélanome, cette étude met en évidence l'intérêt thérapeutique de l'administration par voie intraveineuse d'un agoniste de la protéine STING lié à un polymère via un lien sensible à la cathepsine
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.