LAUSR

Description Making CAR T cells in vivo Cardiac fibrosis is the stiffening and scarring of heart tissue and can be fatal. Rurik et al. designed an immunotherapy strategy to generate transient chimeric antigen receptor (CAR) T cells that can recognize the fibrotic cells in the heart (see the Perspective by Gao and Chen). By injecting CD5-targeted lipid nanoparticles containing the messenger RNA (mRNA) instructions needed to reprogram T lymphocytes, the researchers were able to generate therapeutic CAR T cells entirely inside the body. Analysis of a mouse model of heart disease revealed that the approach was successful in reducing fibrosis and restoring cardiac function. The ability to produce CAR T cells in vivo using modified mRNA may have a number of therapeutic applications. —PNK In vivo generation of CAR T cells by delivery of modified mRNA improves recovery in a mouse model of heart failure. Fibrosis affects millions of people with cardiac disease. We developed a therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified messenger RNA (mRNA) in T cell–targeted lipid nanoparticles (LNPs). The efficacy of these in vivo–reprogrammed CAR T cells was evaluated by injecting CD5-targeted LNPs into a mouse model of heart failure. Efficient delivery of modified mRNA encoding the CAR to T lymphocytes was observed, which produced transient, effective CAR T cells in vivo. Antifibrotic CAR T cells exhibited trogocytosis and retained the target antigen as they accumulated in the spleen. Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury. In vivo generation of CAR T cells may hold promise as a therapeutic platform to treat various diseases.