Cardiac disease afflicts millions of people globally and is hallmarked by substantial alterations to constituent cells. Fibroblasts are mesenchymal cells of particular interest within the diseased heart because they contribute to pathogenic fibrosis (stiffening of the matrix) and serve as pro-inflammatory signaling hubs. Following injury fibroblasts proliferate and activate, fundamentally changing their molecular signature. Through this dissertation, I will demonstrate how these unique molecular differences (namely fibroblast activation protein or FAP) can be used as a target for redirected therapeutic lymphocytes. First, to address the significant clinical burden of cardiac fibrosis in chronic heart diseases, I developed a novel approach to generate anti-fibrotic chimeric antigen receptor (CAR) T cells entirely within the body using modified mRNA packaged in T cell-targeted lipid nanoparticles (tLNP). These transiently engineered cytolytic T effector cells eliminate the pathogenic activated fibroblasts thereby improving the heart’s function in a mouse model of pressure-overload injury. I next evaluated FAP CAR T cells in three musculoskeletal diseases where fibroblasts are thought to be pathogenic (fibrodysplasia ossificans progressiva, Duchenne’s muscular dystrophy, and rheumatoid arthritis). Treatment of these diseases displayed mixed results with arthritis providing the most tantalizing evidence of efficacy. I next asked whether recruiting excess regulatory T (Treg) cells to activated fibroblasts in the acutely injured heart would interrupt the immuno-fibrotic axis that is a driver of maladaptive healing. I demonstrate in two ischemic injury models that boosting Treg recruitment directly to the activated fibroblasts in the acutely injured heart using the FAP CAR benefits tissue recovery. These exciting proof-of-concept experiments using engineered lymphocytes pave the way for multiple therapeutics, spanning acute and chronic cardiac diseases. Importantly, the tLNP/mRNA technology streamlines manufacturing and enables dosing for engineering lymphocytes entirely within the body in a cost-effective way. These tools enable more precise studies of injured tissues, for example the individual pathologic contributions of different activated fibroblasts subpopulations. Altogether I propose a set of engineered T cells, each designed to modulate different aspects of heart disease, with strong implications for the treatment of many other diseases.