Emerging mRNA therapies for cardiac fibrosis

Cardiac fibrosis remains an unmet clinical need that has so far proven difficult to eliminate using current therapies. As such, novel technologies are needed that can target the pathological fibroblasts responsible for fibrosis and adverse tissue remodeling. mRNA encapsulated in lipid nanoparticles (LNPs) is an emerging technology that could offer a solution to this problem. Indeed, this strategy has already shown clinical success with the mRNA COVID-19 vaccines. In this AJP perspective, we discuss how this technology can be leveraged to specifically target cardiac fibrosis via several complementary strategies. First, we discuss the successful preclinical studies in a mouse model of cardiac injury to use T cell-targeted LNPs to produce anti-fibroblast chimeric antigen receptor T (CAR T) cells in vivo that could effectively reduce cardiac fibrosis. Next, we discuss how these T cell-targeted LNPs could be used to generate T regulatory cells (T-regs), which could migrate to areas of active fibrosis and dampen inflammation through paracrine effects as an alternative to active fibroblast killing by CAR T cells. Finally, we conclude with thoughts on directly targeting pathological fibroblasts to deliver RNAs that could interfere with fibroblast activation and activity. We hope this discussion serves as a catalyst for finding approaches that harness the power of mRNA and LNPs to eliminate cardiac fibrosis and treat other fibrotic diseases amenable to such interventions.NEW & NOTEWORTHY Cardiac fibrosis has few specific interventions available for effective treatment. mRNA encapsulated in lipid nanoparticles could provide a novel solution for treating cardiac fibrosis. This AJP perspective discusses what possible strategies could rely on this technology, from in vivo-produced CAR T cells that kill pathological fibroblasts to in vivo-produced T regulatory cells that dampen the concomitant profibrotic inflammatory cells contributing to remodeling, directly targeting fibroblasts and eliminating them or silencing profibrotic pathways.