Synthetic mRNA engineering beyond prophylactic infectious disease vaccines: epigenomic and molecular reprogramming of diseased cells

The clinical validation of mRNA-based COVID-19 vaccines in 2020-2021 accelerated the development of synthetic messenger RNA as a precision therapeutic platform beyond infectious disease prevention. Unlike gene therapy approaches that permanently modify genomic DNA, synthetic mRNA enables transient protein expression through programmable molecular engineering. This narrative review examines therapeutic applications of engineered mRNA, emphasizing its epigenomic potential. It discusses key engineering strategies, including nucleoside modifications, codon optimization, untranslated region engineering, cap chemistry, and advances in lipid nanoparticle and alternative delivery systems. Six therapeutic domains are explored: cancer immunotherapy, cardiac regeneration, monogenic diseases, genome and epigenome editing, autoimmune disease, and somatic cell reprogramming. Particular attention is given to mRNA-mediated replacement of chromatin regulators, dCas9-based epigenome editing, epigenetically derived tumor antigens, and transcription-factor-driven cellular reprogramming. The review distinguishes chemical nucleoside modifications from endogenous epitranscriptomic regulation and examines the differences between transient protein expression, heritable but reversible chromatin changes, and permanent genomic modifications. Clinical evidence, discontinued programs, and preclinical developments are critically evaluated. Despite promising advances, major challenges remain regarding delivery specificity, durability, safety, and clinical translation. Overall, synthetic mRNA represents an emerging platform for molecular and epigenetic therapeutic reprogramming beyond vaccination.