A DNA-based nanodevice senses purinergic signaling and drives an immune switch for resolving inflammation.

Purinergic signaling dysregulation (e.g., excessive extracellular ATP, exATP) plays a critical role in the pathology of inflammatory disorders, but current efforts in drug development for blocking purinergic receptors are unsatisfactory. Here, inspired by natural metabolite sensing/signaling system, we develop a DNA origami-based ATP-sensing nanodevice (ND) for fine-tuning purinergic signaling and immune homeostasis. This ND composes a tubular DNA origami equipped with ATP sensors and the catalytic subunits (ENPP1-CD73 pairs), which can sense high levels of exATP and then expose the catalytic subunits for metabolizing exATP to adenosine, thereby driving an immune switch from exATP-mediated proinflammatory signals to adenosine-mediated immunosuppressive signals. Further surface displaying of ND on the monocytes (ND@Monos) enables its active inflamed site-targeting to restore immunometabolic hemostasis and reduce inflammation in diverse models in vivo. This study highlights that design of metabolite-sensing NDs is a promising strategy for controlling the homeostasis of cell metabolism and the immune response.