Silicate-based therapy for inflammatory dilated cardiomyopathy by inhibiting the vicious cycle of immune inflammation via FOXO signaling

Abstract

Inflammatory dilated cardiomyopathy (iDCM) represents a severe immune-related condition provoked by the progression of myocarditis. In patients suffering from myocarditis, a vicious cycle of inflammation orchestrated by CD4⁺ T cells, neutrophils, and fibroblasts is the culprit that drives the deterioration of myocarditis into iDCM. This study designed composite microneedles and ion solutions using calcium silicate bioceramics, which deliver SiO₃²⁻ directly into myocardial tissue or indirectly via systemic circulation. These interventions modulate the cell microenvironment by regulating CD4⁺ T/T helper 17 (T_H17) cells and their interactions with neutrophils and fibroblasts through the forkhead box O (FOXO) signaling pathway. Specifically, SiO₃²⁻ inhibits the hyperdifferentiation of CD4⁺ T cells to T_H17 cells by regulating FOXO1 and neutrophils to neutrophil extracellular traps as well as fibroblasts to myofibroblasts by regulating FOXO3, thereby ultimately disrupting the vicious cycle of myocardial inflammation and subsequent fibrotic lesions in iDCM. This discovery indicates that the biomaterial-based strategy may have great potential for the treatment of iDCM.