• In the current study, Rurik et al. 1 developed a novel immunotherapy strategy to reduce fibrosis and restore cardiac function in a mouse model of heart failure (HF). To this aim, T cells were temporarily reprogrammed to attack activated heart fibroblasts. Transient engineered chimeric antigen receptor (CAR) T cells were generated in vivo, inducing the T cells to produce their own CAR. Specifically, mRNA encoding a T-cell receptor targeting the fibroblast activation protein (FAP) was encapsulated within lipid nanoparticles (LNPs) that were covered with antibodies against CD5, a receptor naturally expressed by T cells (CD5/LNP-FAPCAR).• CD5-targeted LNPs were shown to deliver their mRNA cargo to 83% of cultured murine T cells that expressed fibroblast activation protein chimeric antigen receptor (FAPCAR) after exposure to CD5/LNP-FAPCAR. FAPCAR expression peaked at 24 h and rapidly declined over the following days. In vitro, these LNP-generated CAR T cells were able to effectively kill FAP-expressing target cells in a dose-dependent manner. Gene transfer through targeted LNPs was also possible in human T cells with an efficiency ranging from 89 to 93%.

• The efficacy of in vivo reprogrammed CAR T cells was evaluated in an established hypertensive model of cardiac injury and fibrosis produced by infusion of angiotensin II/phenylephrine (AngII/PE). Mice were treated for 1 week to allow fibrosis development before injecting CD5/LNP-FAPCAR. Forty-eight hours after injection, a consistent population of FAPCAR-positive T cells (18–25%) were found in mice that received CD5/LNP-FAPCAR. Importantly, FAPCAR expression was transient in this setting, as no FAPCAR expression was found in splenic T cells 1 week after injection.