Shining a light on pyroptosis in cancer chemotherapy by multi-modal imaging with a dual-channel nanoreporter

Pyroptosis is an inflammatory programmed cell death pathway and associated with anti-tumor effects of chemotherapy. In vivo monitoring of pyroptosis is critical for evaluating the therapeutic efficacy and understanding the pyroptosis dynamics within tumors. However, the pyroptosis involves different pathways and there have been no reported methods to monitor the different pyroptosis pathways in vivo. To fill this gap, we designed a dual-activable and multi-modal nanoreporter (CRP) to monitor the intratumoral activation of different pyroptosis pathways during cancer chemotherapy, including caspase-1/gasdermin D and caspase-3/gasdermin E signal axes. Upon activated by caspase-1 and 3, CRP emits two variable near-infrared fluorescent (NIRF) signals, respectively. The changes in dual-channel NIRF signals of CRP are well correlated with intratumoral caspase-1/3 activation levels during cancer chemotherapy, which non-invasively reveals the pyroptosis status in vivo. Concurrently, the stationary magnetic resonance (MR) and magnetic particle (MP) signals offer an efficient self-calibrating method for the determination of pyroptosis. Thus, this study presents the first dual-activable and multi-modal probes for in vivo imaging of pyroptosis by tracking enzyme dynamics, thereby bridging pyroptosis monitoring from experimental research to clinical translation toward immunogenic death-guided precision oncology, and also provides a novel design strategy for molecular imaging of other biomarkers.