Abstract
The sequestration of nanoparticles by mononuclear phagocyte system is a challenge for the use of nanotherapy for treating cardiovascular diseases due to the conventionally perceived loss of therapeutic potency. Here, we revitalize cardiovascular nanotherapy by unlocking an alternative route in which nanomedicines are redirected 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 splenogenic nature of recruited monocytes upon myocardial reperfusion in the 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 that is initially induced in the spleen and orchestrates functional changes in myocardial macrophages. Spleen-related induction of IRF7 is also valid in human myocardial reperfusion scenarios. In addition, in a murine preclinical model of male mice, temporal inhibition of splenic IRF7 through the designed spleen-targeting erythrosome engineered with the targeting peptide RP182, termed as STEER nanoparticles, mitigates the acute-stage innate immune responses and improves the cardiac function in the long term. In contrast, systemic inhibition, genetic knockout of IRF7 or absolute depletion of splenic monocytes does not have therapeutic benefits, indicating the superiority of nanoparticle-based targeted treatment. These findings establish the spleen as a naturally favored site for nanoparticle-based treatments, offering promising avenues for managing myocardial reperfusion injury.