Cardiac immunomodulatory therapy via T cell-targeted RNA interference for treatment of myocardial infarction

Modulation of adaptive immunity represents a promising therapeutic strategy for reconstructing a favorable immune microenvironment and preventing adverse remodeling after myocardial infarction (MI). Here, we established a nanotherapeutic platform for systemic modulation of T cell immunity to promote cardiac repair after MI. Specifically, we engineered anti-CD4 antibody-modified lipid nanoparticles loaded with small interfering RNA targeting interferon gamma (aCD4-iLNPs) to selectively modulate CD4 + T cells in vivo. Systemic administration of aCD4-iLNPs enabled efficient delivery to CD4 + T cells, resulting in a shift in the Th1/Th2 balance toward an anti-inflammatory phenotype. This immune modulation increased Th2 cell recruitment to the infarcted heart, activated anti-inflammatory pathways, attenuated adverse remodeling, and restored cardiac function within 4 weeks post-MI. These findings demonstrate that systemic CD4 + T cell-targeted RNA interference of Ifng can therapeutically modulate adaptive immunity and may serve as a promising cardiac immunomodulatory strategy for MI.