In Vivo Immunomodulatory Programming of Circulating Myeloid Cells via Itaconic Acid Liposomes to Mitigate Myocarditis

Myocarditis is fundamentally characterized by the excessive infiltration of inflammatory cells (monocytes and macrophages) within the myocardium, posing a substantial risk of progressive cardiac dysfunction. Blocking the C–C motif chemokine receptor 2 (CCR2) pathway to curtail the infiltration of CCR2+ monocytes can suppress the immune response; nevertheless, these approaches may unwittingly impede the normal migration and activation of myeloid cells, potentially undermining the body’s immune defenses. To address this backdrop, we designed itaconic acid liposomes (ITA-Lipo) to modulate the immune function of CCR2+ myeloid cells and thereby alleviate myocarditis. It was found that ITA-C4 Lipo could not only inhibit the differentiation of monocytes and macrophages into a pro-inflammatory phenotype but also significantly facilitate the hitchhiking migration toward the myocardium via enhancing the expression of CCR2. In the doxorubicin (DOX)-induced mice myocarditis model, ITA-C4 Lipo enhanced the homeostasis of myocardial cells and reduced relevant blood indicators. The cardiac function was recovered by improving left ventricular ejection fraction (LVEF) and ventricular fractional shortening (LVFS), resulting in the extension of overall mice survival. Anti-inflammatory pathway validation demonstrated that ITA-C4 Lipo can modulate the phenotype of macrophages and activate the KEAP1-Nrf2 pathway, reducing the expression of IL-1β. These findings underscore the significance of ITA liposomes in regulating the polarization of myeloid cells during their chemotaxis to the inflammatory focus, representing a promising therapeutic strategy for myocarditis.