Abstract Body: Bromodomain-containing protein 4 (BRD4) is an effector of transforming growth factor-β (TGF-β) signaling. Upon injury, BRD4 stimulates the differentiation of quiescent cardiac fibroblasts into activated fibroblasts. These activated fibroblasts unfavorably remodel the myocardium by depositing excess extracellular matrix. Here, we reported lipid nanoparticles (LNPs) loaded with small interference RNA against BRD4 (siBRD4) to deactivate fibroblasts after cardiac injury. Because fibroblast activation protein (FAP) is a biomarker of activated fibroblasts, we conjugated anti-FAP antibodies on the LNPs for targeted delivery to activated fibroblasts. Systemic administration of these targeted siBRD4-loaded LNPs inhibited fibroblast activation, reduced fibrosis, and improved cardiac functions in rodent models of myocardial infarction and cardiac fibrosis. Single-nucleus RNA sequencing and cytokine analysis revealed that this therapy further converted the pro-fibrotic and pro-inflammatory microenvironment to a pro-resolution and pro-regeneration one. The safety and toxicity of this nanomedicine were tested in nonhuman primates.