Chemically synthesized, non-capped and non-polyadenylated peptide-coding RNA efficiently induces antigen-specific...

Recombinant in vitro-transcribed mRNA is broadly used for vaccination and is evaluated in numerous clinical studies for multiple indications. Typical features of mRNA are the 5' cap, 5' untranslated region, start and stop codons, 3' untranslated region and 3' poly(A) tail. Here, contrary to current dogma, we show that short, chemically synthesized RNA oligonucleotides lacking some or all of these features are efficiently translated when they encode epitopes recognized by CD8⁺ T cells. In particular, one design that we termed ChemRNA with the structure 5'-OH-AUG-coding sequence-3'-OH strongly stimulates antigen-specific CD8⁺ T cells both in vitro and in vivo. Our results challenge the current understanding of canonical mRNA structure and introduce the possibility that defective or supposedly non-coding RNA may encode human and murine major histocompatibility complex class I-associated peptides. Moreover, ChemRNA could help overcome challenges associated with the design and purification of individualized anti-cancer vaccines.