Identify splenic IRF7 as nanotherapy target for tele-conditioning myocardial reperfusion injury

Abstract Sequestration of nanoparticles (NPs) by the mononuclear phagocyte systems challenges nanotherapy for cardiovascular diseases, due to conventionally perceived loss of therapeutic potency. Here, we revitalize cardiovascular nanotherapy through unlocking an alternative routine by re-directing nanomedicines to the spleen, leveraging its potential as a highly efficient and targeted site for remote conditioning, or tele-conditioning, myocardial reperfusion injury. The theoretical foundation underpinning is the spleen-genic nature of recruited monocytes upon myocardial reperfusion in acute-stage, which is confirmed through murine heterotopic spleen transplantation. Single-cell RNA-seq analysis identifies IRF7 as a pivotal mediator in the spleen-heart communication network, activated initially in the spleen and orchestrating functional changes in myocardial macrophages. Spleen correlated activation of IRF7 is also valid in clinically relevant myocardial reperfusion scenario in human. And in murine preclinical model, temporal inhibition of splenic IRF7 through the designed spleen targeting erythrosome engineered with targeting peptide RP182, termed as STEER NPs, mitigate the acute-stage innate immune responses and improve the cardiac function in long term. Contrarily, the therapeutic benefits are not observed from systemic inhibition, genetic knockout of IRF7 or absolute depletion of splenic monocytes, indicating the superiority of the NP-based targeted treatment settings. These findings establish the spleen as a naturally favored site for NP-based treatments, offering promising avenues for managing myocardial reperfusion injury.